Water Vinyl Chloride Chloride Vinyle Eau ENG - Canada

Guidelines for Canadian Drinking Water Quality

Guideline Technical Document

Vinyl chloride

Health Canada is the federal department responsible for helping the people of Canada

maintain and improve their health. We assess the safety of drugs and many consumer

products, help improve the safety of food, and provide information to Canadians to help

them make healthy decisions. We provide health services to First Nations people and to

Inuit communities. We work with the provinces to ensure our health care system serves the

needs of Canadians.

Published by authority of the Minister of Health.

Guidelines for Canadian Drinking Water Quality: Guideline Technical Document – Vinyl

Chloride

is available on Internet at the following address:

www.healthcanada.gc.ca

Également disponible en français sous le titre :

Recommandations pour la qualité de l’eau potable au Canada : Document technique – Le

chlorure de vinyle

This publication can be made available on request in a variety of alternative formats.

© Her Majesty the Queen in Right of Canada,

represented by the Minister of Health, 2013

This publication may be reproduced without permission provided the source is fully

acknowledged.

Pub. Number: 130479

Cat.: H144-13/6-2013E-PDF

ISBN: 978-1-100-23003-0

Guidelines for Canadian Drinking Water Quality Guideline Technical Document Vinyl Chloride Prepared by the

Federal-Provincial-Territorial Committee on

Drinking Water

of the

Federal-Provincial-Territorial Committee on

Health and the Environment

Health Canada

Ottawa, Ontario

March, 2013

This document may be cited as follows:

Health Canada (2013). Guidelines for Canadian Drinking Water Quality: Guideline Technical

Document — Vinyl chloride. Water and Air Quality Bureau, Healthy Environments and

Consumer Safety Branch, Health Canada, Ottawa, Ontario. (Catalogue No H144-13/6-2013E-

PDF).

The document was prepared by the Federal-Provincial-Territorial Committee on Drinking Water

of the Federal-Provincial-Territorial Committee on Health and the Environment.

Any questions or comments on this document may be directed to:

Water and Air Quality Bureau

Healthy Environments and Consumer Safety Branch

Health Canada

269 Laurier Avenue West, Address Locator 4903D

Ottawa, Ontario

Canada K1A 0K9

Tel.: 613-948-2566

Fax: 613-952-2574

E-mail: [email protected]

Other Guideline Technical Documents for the Guidelines for Canadian Drinking Water Quality

can be found on the following web page: www.healthcanada.gc.ca/waterquality

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Guidelines for Canadian Drinking Water Quality: Guideline Technical Document

ii

Table of Contents

Part I. Overview and Application................................................................................................ 1

1.0 Guideline ............................................................................................................................. 1

2.0 Executive summary ............................................................................................................. 1 2.1 Health effects .......................................................................................................... 1 2.2 Exposure ................................................................................................................. 1

2.3 Analysis and treatment ............................................................................................ 2

3.0 Application of the guideline ................................................................................................ 2 3.1 Monitoring .............................................................................................................. 3

Part II. Science and Technical Considerations .......................................................................... 4

4.0 Identity, use and sources in the environment ...................................................................... 4 4.1 Identity .................................................................................................................... 4

4.2 Major uses and sources ........................................................................................... 4 4.3 Environmental fate .................................................................................................. 5

5.0 Exposure .............................................................................................................................. 6

5.1 Water ....................................................................................................................... 7

5.1.1 Leaching from polyvinyl chloride pipes .................................................... 8 5.2 Food ........................................................................................................................ 9 5.3 Air ........................................................................................................................... 9

5.4 Soil ........................................................................................................................ 10 5.5 Multi-route exposure through drinking water ....................................................... 10

6.0 Analytical methods............................................................................................................ 10

7.0 Treatment technology and distribution system considerations ......................................... 11 7.1 Municipal scale ..................................................................................................... 12

7.1.1 Air stripping and PTA .............................................................................. 12

7.1.2 Granular activated carbon ........................................................................ 13 7.1.3 Ozonation and advanced oxidation processes.......................................... 14

7.1.4 Emerging technologies............................................................................. 15 7.1.5 Distribution system materials: PVC/CPVC ............................................. 15

7.2 Residential scale.................................................................................................... 18

8.0 Kinetics and metabolism ................................................................................................... 19 8.1 Absorption............................................................................................................. 19

8.1.1 Experimental animals............................................................................... 19 8.1.2 Humans .................................................................................................... 19

8.2 Metabolism ........................................................................................................... 19

8.3 Distribution and excretion..................................................................................... 20 8.4 PBPK modeling .................................................................................................... 21

Vinyl chloride (March, 2013)

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iii

9.0 Health effects .................................................................................................................... 23

9.1 Effects in humans .................................................................................................. 23 9.1.1 Acute effects ............................................................................................ 23 9.1.2 Chronic effects and cancer epidemiology ................................................ 23 9.1.3 Non-cancer endpoint epidemiology ......................................................... 26

9.1.4 Mutagenicity/genotoxicity ....................................................................... 27 9.1.5 Reproductive and developmental toxicity ............................................... 28 9.1.6 Children’s sensitivity ............................................................................... 28

9.2 Effects in experimental animals and in vitro ........................................................ 28 9.2.1 Acute effects ............................................................................................ 28

9.2.2 Subchronic exposure ................................................................................ 28 9.2.3 Long-term exposure and carcinogenicity ................................................. 29

9.2.4 Mutagenicity/genotoxicity ....................................................................... 31 9.2.4.1 In vitro ....................................................................................... 32 9.2.4.2 In vivo ........................................................................................ 32

9.2.5 Reproductive and developmental toxicity ............................................... 33

9.2.6 Juvenile sensitivity ................................................................................... 34 9.3 Mode of action ...................................................................................................... 35

10.0 Classification and assessment ........................................................................................... 36 10.1 Cancer risk assessment ......................................................................................... 36 10.2 Non-cancer risk assessment .................................................................................. 38

10.3 Comparison of cancer and non-cancer risk assessments ...................................... 40

10.4 International considerations .................................................................................. 40

11.0 Rationale ........................................................................................................................... 41

12.0 References ......................................................................................................................... 42

Appendix A: List of acronyms ...................................................................................................... 58

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1

March, 2013

Vinyl Chloride

Part I. Overview and Application

1.0 Guideline The maximum acceptable concentration (MAC) for vinyl chloride in drinking water is

0.002 mg/L (2 μg/L). Every effort should be made to maintain vinyl chloride levels in drinking

water as low as reasonably achievable (or ALARA).

2.0 Executive summary Vinyl chloride is primarily a synthetic chemical. It can enter drinking water through

leaching from polyvinyl chloride (PVC) pipes, from industrial discharges from chemical and

latex manufacturing plants, or as a result of the biodegradation of synthetic solvents. Only one

PVC manufacturing facility currently exists in Canada.

This guideline technical document reviews and assesses all identified health risks

associated with vinyl chloride in drinking water, incorporating all relevant routes of exposure

from drinking water—namely, ingestion as well as inhalation and skin absorption from

showering and bathing.

It assesses new studies and approaches and takes into consideration the availability of

appropriate treatment technology in order to establish a maximum acceptable concentration that

is protective of human health, measurable and achievable by both municipal and residential scale

treatment technologies. Based on this review, the drinking water guideline for vinyl chloride has

been established at a maximum acceptable concentration of 0.002 mg/L (2 μg/L).

2.1 Health effects

Vinyl chloride is classified as a human carcinogen, with sufficient evidence in both

humans and animals. Vinyl chloride exposure has been linked with liver and neurological

effects, in both humans (at occupational exposure levels) and animals. Liver cancer is the most

serious endpoint that follows exposure from ingestion or inhalation of vinyl chloride.

The MAC has been established taking into consideration the most vulnerable population:

Evidence from animal studies suggests that very young children (less than 5 weeks of age) may

be twice as sensitive to the carcinogenic effects of vinyl chloride as adults. However, there are no

human studies supporting these findings.

2.2 Exposure

The general population is primarily exposed to vinyl chloride from inhalation of ambient

air and the ingestion of items packaged in PVC containers, which may leach vinyl chloride.

Exposure can also occur from drinking water, from sources of contamination in the environment,

or from leaching of PVC pipes in the distribution system. However, vinyl chloride is rarely

detected in Canadian drinking water supplies. There are no Canadian data on vinyl chloride

levels in sediment, sewage or consumer products. Canadians may also be exposed to vinyl

chloride from drinking water through inhalation and dermal absorption.

Vinyl Chloride (March 2013)

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2

2.3 Analysis and treatment

The establishment of a drinking water guideline must take into consideration the ability

to both measure the contaminant and remove it from drinking water supplies. Vinyl chloride can

be reliably measured in drinking water at the MAC.

At the municipal level, conventional treatment techniques are not effective at removing

vinyl chloride. The best available technology for removing vinyl chloride is packed tower

aeration. Taking into consideration currently available technologies, municipal treatment plant

are expected to be able to consistently achieve concentrations below the MAC.

At the residential level, although there are no treatment units currently certified to remove

vinyl chloride, treatment devices using treatment technologies such as activated carbon may

remove vinyl chloride below the MAC if two or more units are installed in series.

3.0 Application of the guideline Note: Specific guidance related to the implementation of drinking water guidelines should be

obtained from the appropriate drinking water authority in the affected jurisdiction.

Vinyl chloride is a human carcinogen, which means that exposure to any level in drinking

water may increase the risk of cancer. Jurisdictions may establish more stringent limits than the

MAC.

Generally, vinyl chloride is not a concern for the majority of Canadians who rely on

surface water as their source of drinking water, because it volatilizes easily. However, as vinyl

chloride released to the ground does not adsorb onto soil, any that does not evaporate migrates

readily to groundwater, where it is expected to remain for months to years. Vinyl chloride is

usually only detected in groundwater in the vicinity of landfills and where there have been spills

of vinyl chloride or chlorinated precursor compounds.

Vinyl chloride may also leach from polyvinyl chloride pipes used in the distribution and

plumbing systems. To minimize levels of vinyl chloride from these systems, materials in contact

with drinking water should be certified to ANSI/NSF Standard 61.

The drinking water guideline is based on lifetime exposure (70 years) to vinyl chloride

from drinking water. For drinking water supplies that occasionally experience short-term

exceedances above the guideline value, it is suggested that a plan be developed and implemented

to address these situations. For more significant, long-term exceedances that cannot be addressed

through treatment, it is suggested that alternative sources of water for drinking, showering, and

bathing be considered. For infants less than 5 weeks of age, who may be more sensitive to the

health effects of vinyl chloride, concentrations in drinking water should be kept as low as

reasonably achievable.

The guideline for a carcinogen is normally established at a level at which the increased

cancer risk is “essentially negligible” when a person is exposed at that level in drinking water

over a lifetime. In the context of drinking water guidelines, Health Canada has defined this term

as a range from one new cancer above background levels per 100 000 people to one new cancer

above background levels per 1 million people (i.e., 10−5

–10−6

). The estimated lifetime risk

associated with ingestion of water containing vinyl chloride at the MAC is 5.0 × 10-5

which is

above the range that is considered to represent “essentially negligible” risk. However, the MAC

for vinyl chloride is a risk-managed value based on analytical achievability. Considering that it


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3

exceeds the health-based value, every effort should be made to maintain vinyl chloride levels in

drinking water as low as reasonably achievable (or ALARA).

3.1 Monitoring

Groundwater sources should be characterized to determine if vinyl chloride is present,

especially if the land use history is unknown. Quarterly monitoring for vinyl chloride should be

conducted for groundwater sources that are or may have been impacted by landfill leachate,

spills of vinyl chloride or chlorinated VOCs.

Although newer pipes and components are required to meet standards that limit leaching

of contaminants, polyvinyl chloride water mains manufactured prior to 1977 are prone to

leaching vinyl chloride because they often contain higher concentrations of unpolymerized vinyl

chloride monomer.

It is recommended that distribution systems with these older PVC pipes be monitored for

vinyl chloride. Quarterly monitoring for vinyl chloride should be undertaken in the areas of the

distribution system where older PVC pipes are located, specifically at locations with the

maximum residence time (e.g., dead ends). Utilities that have baseline data indicating that vinyl

chloride is not present within the distribution system may conduct less frequent monitoring.

Jurisdictions may consider reduced sampling if an appropriate flushing protocol is in place.

In the event that monitoring data show elevated levels vinyl chloride, it is suggested that

a plan be developed and implemented to address these situations.


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4

Part II. Science and Technical Considerations

4.0 Identity, use and sources in the environment

4.1 Identity

Vinyl chloride (CH2CHCl; Chemical Abstracts Service registry number 75-01-4) is a

colourless, flammable, explosive gas with a boiling point of -13.4°C and high volatility, as

indicated by its Henry’s Law constant of 2.8 kPa·m3/mol at 25°C and vapour pressure of

362.6 kPa at 20°C (U.S. EPA, 2000a). Vinyl chloride, also known as vinyl chloride monomer,

chloroethene, monochloroethylene or ethylene monochloride, has a relative molecular weight of

62.5 (OEHHA, 2000; ATSDR, 2006). It is slightly soluble in water (1.1 g/L at 28°C) but highly

soluble in fats and organic solvents. It polymerizes in light and in the presence of a catalyst. On

combustion, it degrades to hydrogen chloride, carbon dioxide and traces of phosgene. Vinyl

chloride has a pleasant, sweet odour at high concentrations (ATSDR, 2006; IARC, 2008). In air,

1 part per million (ppm) of vinyl chloride corresponds to 2.6 mg/m3 at 25°C and one atm of

pressure.

4.2 Major uses and sources

Vinyl chloride can primarily enter the environment through anthropogenic sources, and

may also be formed naturally in soil (Keppler et al., 2002). It is now produced and used with

stringent methods for containment and recovery. Vinyl chloride can enter drinking water through

leaching of the entrapped monomer from polyvinyl chloride (PVC) pipe. Releases to the aquatic

environment are primarily a result of industrial discharges from chemical and latex

manufacturing plants (IARC, 1979). Vinyl chloride can also be formed in groundwater and the

environment by biodegradation of synthetic solvents, such as trichlorethene, trichloroethane and

tetrachloroethene (Parsons et al., 1984; OEHHA, 2000; ATSDR, 2006).

Between 1986 and 1999, Canadian industrial manufacturing capacity for vinyl chloride

ranged between 373 and 550 kilotonnes per year, whereas production rates ranged between 270

and 439 kilotonnes per year (CIS, 1999). The closing of vinyl chloride manufacturing plants has

decreased Canadian production of vinyl chloride since 2000: the Dow Chemical Company closed

its vinyl chloride facility in Sarnia, Ontario, in the early 1990s and its facility in Fort

Saskatchewan, Alberta, in 2006; BF Goodrich closed its Shawinigan, Québec, plant in 1993, and

Royal Polymer closed its plant in Sarnia, Ontario, in 2009. Only one PVC manufacturing facility

currently exists in Canada located in Niagara Falls, Ontario (Environment Canada, 2008).

In 1982, 86% of the Canadian production of vinyl chloride was used to manufacture

polyvinyl chloride, 4% was used to manufacture 1,1,1-trichloroethane and 10% was exported

(Environment Canada, 1985). However, between 1986 and 1999, production of PVC increased

while the use of vinyl chloride for 1,1,1-trichloroethane became negligible and the quantity

exported decreased. The importation of PVC into Canada rose from 73 to 440 kilotonnes per

year during that same period. After 1993, nearly 100% of vinyl chloride produced in Canada was

used in the manufacture of PVC (CIS, 1999). The majority of PVC demand in Canada was for

the manufacture of pipe and fittings. Rigid PVC used for pipes and fittings contains little or no

plasticizer when produced for potable water applications. As such, PVC is sometimes called

rigid or unplasticized PVC (Richardson and Edwards, 2009).

PVC is used in electrical wire, insulation and cables, industrial and household equipment,

medical supplies, food packaging materials, building and construction products and piping. In


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5

addition, PVC is used as a raw material in the paper, glass, rubber and automotive industries.

Vinyl chloride and polyvinyl chloride co-polymers are distributed and processed in a variety of

forms, such as dry resins, plastisol, organosol and latex (U.S. EPA, 2000b). Concentrations of

vinyl chloride monomer in PVC were reduced drastically between 1973 and 1975, ranging from

1 to 10 ppm (ECETOC, 1988). A wide variety of foods and drinks are packaged in containers or

film made of polyvinyl chloride or vinyl chloride co-polymers, and residual vinyl chloride may

migrate into food or beverages (ECETOC, 1988). Children’s plastic toys, such as dolls, bath toys

and squeeze toys are often manufactured with PVC. Vinyl chloride has also historically been

detected in the interior of new cars (824 to 3120 μg/m3) (IARC 1979). The vinyl chloride content

in the smoke of USA-manufactured cigarettes and small cigars ranged from 5 to 27 ng per

cigarette (mean concentration of 11.35 ng/cigarette) (Hoffmann et al., 1976).

A PVC manufacturing facility located in Niagara Falls (Thorold), Ontario, released 2489

million litres of wastewater per day to the river between 2005 and 2007 and reported a vinyl

chloride concentration of 1.46 µg/L in the wastewater released to the river (Oxy Vinyl, 2008).

According to National Pollutant Release Inventory data, the total amount of vinyl chloride

released into surface water in 2007 was 0.001 tonnes (NPRI, 2007). Vinyl chloride was

historically released to water in Sarnia, Ontario; however, the amount has decreased since 1998,

and no vinyl chloride release to water has been reported in Sarnia since 2000, with the exception

of 0.297 tonnes in 2003.

Historically, the amount of vinyl chloride released into air peaked at 44 tonnes in 1997

and has since been steadily decreasing. In 2007, 2.7 tonnes of vinyl chloride were emitted to the

atmosphere by major Canadian industrial facilities; the largest vinyl chloride emissions in 2007

occurred in three Ontario cities: Thorold, Sarnia and Guelph. Releases were also regularly

reported for Fort Saskatchewan, Alberta, before the 2006 closure of the vinyl chloride

manufacturing plant there (NPRI, 2007).

Lesage et al. (1993) measured the vinyl chloride levels in leachate from a municipal solid

waste landfill located in Guelph, Ontario: average vinyl chloride concentrations of 14 µg/L and

23 µg/L were found in samples (number not specified) collected in 1988 and 1989, respectively.

In 2007, 0.538 tonnes of vinyl chloride were released to land, with releases occurring in Thorold,

Ontario; Sarnia, Ontario; and Winnipeg, Manitoba (NPRI, 2007).

In a study conducted to investigate the potential for the production of vinyl chloride

through natural soil processes, soil air and ambient air were analyzed for volatile chlorinated

halocarbons. The concentrations of vinyl chloride in the soil air were significantly higher than

those in ambient air, suggesting a natural formation in soil. Given that the vinyl chloride,

trichloroethene and tetrachloroethene concentrations in ambient air were very low, the authors

concluded that the significantly higher concentrations for vinyl chloride in soil air could not be

attributed to ambient air contamination. The authors were able to produce vinyl chloride in the

laboratory during follow up experiments using different pristine soils and model compounds.

The authors proposed that vinyl chloride could be formed during the oxidative degradation of

organic matter in soil, such as through a reaction between humic substances, chloride ions and an

oxidant (ferric ions or hydroxyl radicals). The authors (Keppler et al., 2002) indicated that more

detailed investigations are required to better understand the formation and significance of

naturally produced vinyl chloride in soil.

4.3 Environmental fate

Vinyl chloride is not usually detected in groundwater. Possible sources to groundwater

include landfill leachate as well as spills of vinyl chloride or chlorinated precursor compounds.


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6

Vinyl chloride released to the soil does not adsorb onto soil particles; any that does not evaporate

migrates readily to groundwater, where it can remain for months to years (Parsons et al., 1984).

The half-life of vinyl chloride monomer at a concentration of 1 mg/L in open water at a 1 m

depth is estimated to be 26 minutes, and 90% is lost by evaporation within 96 minutes

(Verschueren, 1984).

Under aerobic conditions, vinyl chloride in samples taken from a shallow aquifer

(groundwater) was readily degraded, with more than 99% being degraded after 108 days and

approximately 65% being mineralized to carbon dioxide (Davis and Carpenter, 1990). Further,

Bradley and Chapelle (2011) reported that even under hypoxic (initial dissolved oxygen

concentrations about 0.1 mg/L) and nominally anoxic (dissolved oxygen minimum detection

limit = 0.01 mg/L) conditions, first-order rates for vinyl chloride biodegradation (mineralization)

were approximately 1 to 2 orders of magnitude higher in hypoxic groundwater sediment

treatments and at least three times higher in hypoxic surface water sediment treatments than in

the respective anoxic conditions.

Under anaerobic conditions, biodegradation of chlorinated compounds can result in vinyl

chloride production. Vinyl chloride may be further degraded to less chlorinated and non-

chlorinated ethenes, and possibly to carbon dioxide and ethane. However, these subsequent

reactions often proceed at a slow rate under anaerobic conditions, and hence vinyl chloride may

persist in groundwater (ATSDR, 2006). For example, Jacobs et al. (2007) reported that at some

U.S. Superfund sites, vinyl chloride has been shown to persist for over 20 years. A pseudo-first

order rate constant of 1.01 × 10-3

(months)-1

and a half-life of 57.2 years were estimated for the

disappearance of vinyl chloride in water microcosms under anaerobic conditions without

bioenhancement. However, anaerobic biodegradation has been shown to occur more rapidly

under methanogenic or Fe(III)-reducing conditions (Bradley and Chapelle, 1996, 1997). Bradley

and Chapelle (1996) reported that the addition of Fe(III) as Fe-EDTA to anaerobic aquifer

microcosms resulted in rapid mineralization (15-34%) of [1,2-14

C]vinyl chloride to 14

CO2 within

a period of 84 hours. Rates of vinyl chloride mineralization in Fe-EDTA-amended microcosms

were comparable to those observed in aerobic microcosms (22-39% in 84 hours). The authors

concluded that the addition of chelated Fe(III) may be an effective treatment for enhanced

bioremediation of vinyl chloride contaminated ground water systems. In another study by

Bradley and Chapelle (1997), the recovery of [1,2-14

C]VC radioactivity as 14

CO2 ranged from

5% to 44% in methanogenic microcosms and from 8% to 100% in Fe(III)-reducing microcosms

for a 37 day period.

The low boiling point, high vapour pressure and low water solubility of vinyl chloride

indicate that any vinyl chloride released to surface water will migrate rapidly to air. In waters

containing photosensitizers, such as humic materials, sensitized photodegradation may also be

important removal pathway (ATSDR, 2006).

When released to the atmosphere, vinyl chloride is expected to be removed by reaction

with photochemically generated hydroxyl radicals (half-life of 1–2 days) liberating reaction

products such as hydrochloric acid, formaldehyde, formyl chloride, acetylene,

chloroacetaldehyde, chloroacetylchloranil, and chloroethylene epoxide (ATSDR, 2006).

5.0 Exposure The general population is primarily exposed to vinyl chloride from inhalation of ambient

air and the ingestion of items packaged in PVC containers, from which vinyl chloride can leach


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7

(ATSDR, 2006). Canadian data on vinyl chloride levels in sediment or sewage were not located.

No published quantitative data on vinyl chloride exposure from plastic toys are available.

5.1 Water

In a national survey of 30 Canadian water treatment facilities conducted in 1979, vinyl

chloride was detected at < 1 µg/L in one sample each of treated and raw water collected in the

months of November and December but was not present in samples collected in August or

September (Otson et al., 1982).

In Alberta, out of 1622 samples collected since January 1, 2000, only two detections of

vinyl chloride were reported from provincial parks treated drinking water; both detections (0.11

and 0.5 µg/L) were at or near the method detection limit (MDL), with the “largest” MDL in the

data being 1.0 µg/L (Alberta Environment, 2009).

In New Brunswick, vinyl chloride was not detected in any drinking water supplies from

1994 to 2008 (New Brunswick Department of Environment, 2009).

In Nova Scotia, testing was conducted between March 2002 and April 2008 in 47 of 85

municipal drinking water treatment facilities; a total of 202 “non-detect” results for vinyl

chloride were reported, which included 102 raw and 100 treated samples. The MDL ranged from

0.17 µg/L to 1 µg/L (Nova Scotia Department of Environment, 2009).

In Quebec, during the period of 2001–2009, 4824 samples from 276 distribution systems

(mostly serving more than 5000 people) were analysed for vinyl chloride. In total, 4807 results

(99.6%) were reported as being below the MDL, which ranged between 0.02 and 0.6 µg/L,

depending on the laboratory; 17 samples contained vinyl chloride at levels ranging between 0.04

and 3.0 µg/L, with a mean of 0.75 µg/L (Ministère du Développement durable, de

l’Environnement et des Parcs du Québec, 2009).

In Saskatchewan, during the period of 1996–2008, no vinyl chloride was detected in 25

samples from the distribution system (MDL ranged from 0.4 to 1 µg/L) (Saskatchewan Ministry

of Environment, 2009).

The First Nations and Inuit Health Branch of Health Canada reported vinyl chloride

sampling results for both raw and treated water from four provinces (Health Canada, 2009). In

British Columbia, no vinyl chloride was detected in 10 raw water samples (MDL ranged from

0.5 to 1 µg/L) for the period of 2002–2008; however, vinyl chloride was detected in 2 of 920

treated samples at 0.61 and 0.54 µg/L. For Alberta, from 2004 to 2008, vinyl chloride was not

detected in 177 treated drinking water samples; however, it was detected in 1 of 30 raw water

samples at a level below 2 µg/L (MDL ranged from 0.2 to 2 µg/L). In Ontario, vinyl chloride

was not detected in 424 raw water samples (MDL of 0.2 µg/L); however, 1 detection (0.5 µg/L)

out of 1072 samples was reported for treated drinking water during the period of 2001–2009.

Finally, in Manitoba, from 2001 to 2009, no vinyl chloride was detected in 460 samples of raw

water (MDL ranged from 0.2 to 2 µg/L); however, 7 samples of treated drinking water out of 700

contained vinyl chloride at levels ranging from 0.9 to 1.6 µg/L.

Environment Canada (1998) monitored vinyl chloride levels in surface waters and

groundwaters in eastern Canada (Nova Scotia, Prince Edward Island, Newfoundland and New

Brunswick). Between 1985 and 1988, vinyl chloride levels were measured in lakes (n = 86),

ponds (n = 17), reservoirs (n = 29) and rivers and streams (n = 50). The average vinyl chloride

concentration in each of these surface water systems was below the MDL of 5 µg/L

(Environment Canada, 1998). In 141 groundwater samples from various locations throughout the

provinces, vinyl chloride levels were below the MDL of 5 µg/L in all samples (Environment

Canada, 1998).


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5.1.1 Leaching from polyvinyl chloride pipes

Currently, PVC and chlorinated PVC (CPVC) plastic pipes and components are used for

conveying potable water. In the polymerization process, some of the vinyl chloride monomers

are retained in the plastic pipe matrix (PVC or CPVC) as a residue and may be released into the

air or water (WHO, 2004; Richardson and Edwards, 2009). In early field investigation

(Dressman and McFarren, 1978) and experimental studies (Banzer, 1979; Ando and Sayato,

1984) demonstrated the ability of residual vinyl chloride to migrate from water distribution PVC

pipes into the water flowing through them. The extent of leaching is determined by the vinyl

chloride concentrations in the pipe material. In the field study, the highest vinyl chloride

concentrations (1.4 μg/L) consistently occurred in water from pipes manufactured in 1975

whereas the lowest level (0.03 μg/L) was found in the pipes manufactured in 1966 (Dressman

and McFarren, 1978). The amount of vinyl chloride migrating from rigid PVC pipes into

drinking water was found to be directly proportional to the residual level of vinyl chloride in the

pipe itself. Older PVC pipes (pre-1977) may contain vinyl chloride in concentrations up to

600 mg/kg, and have been shown to leach vinyl chloride into drinking water (Beardsley and

Adams, 2003).

There are several solutions to address vinyl chloride leaching from the pre-1977 PVC

pipes that are still in use today, including replacement of pipes, use of drinking water treatment

devices and implementation of flushing protocol. Beardsley and Adams (2003) determined that

the development and implementation of an appropriate flushing protocol is a practical approach

to reduce exposure from vinyl chloride in these pipes. PVC is generally used for cold water

applications for distribution system and premise plumbing pipes and components (i.e., fittings).

The National Plumbing Code of Canada (NPC) allows the use of PVC only for cold water

plumbing applications (NRCC, 2010). CPVC has higher heat resistance and greater mechanical

stability from the chlorination process. Under the NPC, CPVC is permitted for use in both hot

and cold water applications (NRCC, 2010). It is also important to note that the NPC has required

that all plastic pipe meet the Canadian Standards Association’s (CSA) standard for plastic pipes

(CSA, 2009). The CSA standard was revised in 1990 to include a leaching test for vinyl chloride

into drinking water. The CSA B137 series of standards for thermoplastic pressure piping

currently requires that PVC and CPVC pipes and components (e.g. tubing and fittings), used for

drinking water applications, comply with the requirements of NSF/ANSI Standard 61 (CSA,

2009). In order for PVC and CPVC products and materials to be certified to NSF/ANSI Standard

61, they must contain 3.2 mg/kg or less residual vinyl chloride monomer in the product wall,

which is equivalent to 0.2 µg/L of vinyl chloride diffused into water. This acceptance criterion is

the single product allowable concentration (SPAC), which is derived using the contaminant

regulatory values from the U.S. EPA and Health Canada (one tenth of the regulatory value of 2

µg/L) (NSF/ANSI, 2012). Pipes and components meeting NSF/ANSI Standard 61 would be

expected to leach very low concentrations of vinyl chloride into drinking water.

Richardson and Edwards (2009) investigated the leaching and accumulation of vinyl

chloride from static segment/fragment reactors from PVC and CPVC piping used in drinking

water applications. Although the results indicated that the newer PVC reactors leached faster and

accumulated higher concentrations than CPVC, the levels of vinyl chloride concentrations

leached from PVC and CPVC reactors were very low. The results from this study are presented

in greater detail in section 7.1.5.

When PVC pipes were exposed to sunlight at maximum ambient temperatures of 35ºC

the pipes were found to release more than 2.5 µg/L of vinyl chloride into the water. In the


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9

absence of sunlight, no vinyl chloride was released which indicates that environmental

conditions such heat and UV light can adversely affect vinyl chloride release (Al Malack and

Sheikheldin, 2001).

5.2 Food

Vinyl chloride has been shown to migrate from PVC packaging to bottled drinking water.

Benfenati et al. (1991) found that progressive migration of vinyl chloride from the bottle to the

water occurred at a rate of 0.001 µg/L per day. Vinyl chloride levels of 0.013–0.083 µg/L (mean

of 0.048 µg/L) were measured in Italian drinking water bottled in PVC (Benfenati et al., 1991).

There is very little information on concentrations of vinyl chloride in food. The leaching

of vinyl chloride from wet food packaging materials is low; however, vinyl chloride is soluble in

alcohols and mineral oil. The Canadian Food and Drug Regulations prohibit the sale of any food

packaged in materials that leach detectable residues of vinyl chloride monomer, as determined by

an analytical method with a detection limit of 50 µg/kg (Government of Canada, 2011). Vinyl

chloride intake via food and drinks has been estimated to be 0.1 µg/day (Purchase et al., 1985).

5.3 Air

In Alberta, 24-hour average concentrations of vinyl chloride at the perimeter of a vinyl

chloride plant from 1979 to 1984 were 12.9 µg/m3 (5 ppb) 86–98% of the time; 12.9–23.2 µg/m

3

(5–9 ppb) 0.3–4.9% of the time; 25.8–77.4 µg/m3 (10–30 ppb) 0.1–6.5% of the time; and

77.4 µg/m3 (30 ppb) 0.3–2.4% of the time (Environment Canada, 1986). The general public may

be exposed to small amounts of vinyl chloride from inhalation of ambient air in urban areas,

typically in the order of 5 µg/day per person (ECETOC, 1988), with higher amounts in the

vicinity of vinyl chloride and PVC plants.

Of 2560 samples collected at 47 sites in Canada in 2002, vinyl chloride was generally not

detected (< 0.05 µg/m3) in 24-hour samples (Environment Canada, 2004). A maximum 24-hour

concentration of 0.7 µg/m3 was reported for Sarnia, Ontario; Sarnia is an urban area with a

known industrial point source. Based on annual outdoor air data from Montreal, Quebec, the

average 24-hour vinyl chloride concentration was 0.02 µg/m3 for 2001 and 2002 (four sites, eight

samples) (Environment Canada, 2002).

National Air Pollution Surveillance Network stations measured concentrations of vinyl

chloride in ambient air across Canada (Environment Canada, 2006). Between 2003 and 2006,

nearly 99% of all average vinyl chloride concentrations for both rural (4379 of 4447 samples)

and urban centres (7787 of 7879 samples) were reported to be below the MDL of 0.02 µg/m3.

Health Canada measured vinyl chloride levels inside 100 non-smoking homes in

Windsor, Ontario, from 2005 to 2006 (Stocco et al., 2008). The mean indoor vinyl chloride

concentration was 0.062 µg/m3 in the summer and 0.028 µg/m

3 in the winter. Outdoor levels of

vinyl chloride were lower than indoor levels in summer and winter. The mean exposure

concentration was determined to be 0.01 µg/m3 in winter and < 0.001 µg/m

3 in summer (Stocco

et al., 2008).

In a study by Dawson and McAlary (2009), vinyl chloride was detected in 7% of a total

of 1684 North American homes sampled; concentrations up to 1.3 µg/m3 were detected (with

reporting limits ranging from 0.01 to 1.3 µg/m3).

In the United States, indoor air concentrations of vinyl chloride in houses close to

landfills have reached concentrations of up to 1 mg/m3 and have exceeded the maximum

reported concentration in outdoor air for areas adjacent to the landfills. A California monitoring

program that collected 500 samples at two outdoor and four indoor sites downwind of a landfill


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10

reported that the 120 samples containing the highest vinyl chloride concentration (25 μg/m3)

were taken inside homes (Little et al., 1992). An average vinyl chloride concentration of 4 ppb

(10.4 μg/m3) and a maximum of 9.3 ppb (24.2 μg/m

3) were measured in over 500 samples from

69 homes near a co-disposal landfill site in California, while concentrations over the site ranged

from 83 to 12,800 ppm (216–33,280 mg/m3) (Stephens et al., 1986).

5.4 Soil

To establish local background conditions, the Ontario Ministry of the Environment

measured the vinyl chloride concentration in soil samples collected from sites with no known

point sources (OME, 1997). A vinyl chloride concentration of 0.003 µg/g was determined to be

the typical background level in Ontario for agricultural and all other land uses, based on the 90th

percentile concentration measured in soil samples.

5.5 Multi-route exposure through drinking water

A human physiologically based pharmacokinetic (PBPK) model based on Clewell et al.

(2001, 2004) was developed to extrapolate the results from two high-dose oral exposure studies

in rats (Feron et al., 1981; Til et al. 1991) to humans exposed to low concentrations of vinyl

chloride in drinking water. The model was also used to estimate the litre-equivalent (L-eq)

contributions from dermal and inhalation exposure to vinyl chloride when showering and

bathing. Using the external doses generated from the human PBPK model (see Sections 8.4 and

10.1), litre-equivalent contributions from dermal and inhalation exposure during showering or

bathing were estimated by running the human PBPK model for a 30-minute bathing scenario. By

comparing the internal doses generated from dermal and inhalation routes of exposure with the

internal dose from ingestion, the litre-equivalent contributions for dermal and inhalation

exposure were determined to be 1.9 L-eq and 0.4 L-eq, respectively. When added to the standard

Canadian drinking water consumption rate of 1.5 L/day, the total litre-equivalent daily exposure

to vinyl chloride in drinking water was estimated to be 3.8 L-eq. This litre-equivalent daily

exposure was used in both the cancer and non-cancer risk assessments in Section 10.

6.0 Analytical methods The U.S. Environmental Protection Agency (EPA) currently has three approved

analytical methods (Method 502.2 Revision 2.1, Method 524.2 Revision 4.1 and Method 524.3

Version 1.0) for the analysis of vinyl chloride in drinking water (U.S. EPA, 2003, 2009a). These

methods are general methods for the identification and measurement of purgeable volatile

organic compounds (VOCs). The methods use purge and trap procedures, followed by a capillary

gas chromatography (GC) column to separate the analytes. After an elution from the GC column,

the analytes are identified by different detection techniques.

Method 502.2 Revision 2.1 uses a purge and trap capillary GC column equipped with

photoionization detectors (PID) and electrolytic conductivity detectors (ELCD) in series. The

method’s MDL will vary depending on the GC column used and ranges from 0.02 to 0.04 µg/L

for the PID and from 0.01 to 0.18 µg/L for the ELCD.

Method 524.2 Revision 4.1 uses a capillary GC column interfaced with a mass

spectrometer (MS). The method has MDL values between 0.04–0.17 µg/L, depending on the GC

column and the interface used between the GC and MS (U.S. EPA, 1995).


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11

Method 524.3 version 1.0, approved in 2009, uses the GC-MS technique and has a

detection limit of 0.029 µg/L for vinyl chloride. The advantages of the method include an

optimization of the purge and trap parameters, an option for use of selected ion monitoring (SIM)

and the use of solid acid preservatives (U.S. EPA, 2009a).

Two Standard Methods can also be used for the analysis of vinyl chloride in drinking

water (APHA et al., 2005). These methods, SM 6200B and SM 6200C, are based on purge and

trap capillary GC followed by MS detector or PID and ELCD in series, respectively. Method SM

6200B has an MDL of 0.12 µg/L, and SM 6200C has an MDL of 0.025 µg/L. The minimum

quantitation levels, defined as the lowest level that can be quantified accurately using these

methods, are 0.48 µg/L and 0.1 µg/L for methods SM 6200B and SM 6200C, respectively.

A recent study investigating the factors affecting the leaching of vinyl chloride from PVC

and CPVC piping used in drinking water applications reported an MDL of 0.0045 µg/L using

GC-MS in SIM mode (Richardson and Edwards, 2009).

However, the practical quantitation level (PQL) for U.S. EPA-approved methods is

2 µg/L and is based on the capability of laboratories to measure vinyl chloride within reasonable

limits of precision and accuracy at the time of regulation. Current PQL assessments are based on

two approaches: (1) the lowest value for which 75% of laboratories can quantitate within

prescribed accuracy limits based on actual performance data, if the data is sufficient; or (2)

multiplying the upper levels of the MDLs to account for the variability inherent to test methods

and instruments used for analyses, when data is insufficient. In establishing the PQL, the U.S.

EPA considers and prefers the laboratory performance data for methods approved at the time of

the review over the MDL approach (U.S. EPA, 2009d).

In the second 6-year review of existing National Primary Drinking Water Regulations,

the U.S. EPA determined that there was insufficient proficiency testing data to derive PQLs

(U.S. EPA 2009d). Therefore, the U.S. EPA used two other sources to derive an estimated

quantitation level (EQL): a minimum reporting level (MRL) approach and an MDL multiplier

approach based on the approved analytical methods. The EQL is an estimate of the possible

lower bound for a PQL. It is based on statistical analysis of proficiency test results for a method

or the MRL from the dataset. The MRLs represent laboratory analytical limits for a large pool of

laboratories in the U.S. Using the MRLs of more than 139,000 records collected from 1998 to

2005, the U.S. EPA established an EQL of 0.5 µg/L for vinyl chloride, reporting that a high

percentage of the samples achieved a MRL of 0.5 µg/L.

Applying a multiplier of 10 to the upper bounds of the MDL for each of the two approved

analytical methods (502.2 and 524.2), resulted in a possible PQL range of 1.7 to 1.8 µg/L. These

values were slightly below the current PQL of 2 µg/L (U.S. EPA, 2009d). Ultimately, the U.S.

EPA chose not to modify the existing PQL, because the data could not support the adoption of a

lower value (U.S. EPA, 2009d).

There is no equivalent centralised program for the collection and rigorous statistical

analysis of analytical data in Canada. As such, establishing a PQL for Canadian laboratories is

not possible.

7.0 Treatment technology and distribution system considerations Vinyl chloride is typically found in groundwater in the vicinity of landfills and where

there have been spills of vinyl chloride or chlorinated precursor compounds. As such, it is

important to characterize these groundwater sources in order to select the appropriate treatment


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12

for removal of vinyl chloride. The selection of an appropriate treatment process will depend on

many factors, including the characteristics of the raw water supply and the source and

concentration of vinyl chloride.

7.1 Municipal scale

Municipal water filtration plants that rely on conventional treatment techniques

(coagulation, sedimentation, filtration and chlorination) are generally ineffective in reducing

concentrations of VOCs, such as vinyl chloride, in drinking water (Love and Eilers, 1982; Love

et al., 1983; Lykins and Clark, 1994). Two common treatment technologies reported to be

effective for the reduction of most VOCs in drinking water are aeration and adsorption.

Vinyl chloride is a gas under ambient environmental conditions. It has a relatively low

solubility in water and a low capacity to adsorb to particulate matter and sediment. Volatilization

is the most rapid process for the removal of vinyl chloride from surface waters (IPCS, 1999). Its

high Henry’s Law constant (2.8 kPa·m3/mol at 25°C) suggests that vinyl chloride would be very

amenable to removal by air stripping (U.S. EPA, 1985a; Crittenden et al., 1988; Haarhoff and

Cleasby, 1990). The U.S. EPA has identified packed tower aeration (PTA) as the best available

technology (BAT) for vinyl chloride removal from drinking water and considers a 99.9%

reduction to be achievable under all anticipated conditions (U.S. EPA, 1985a, 2009c). WHO

(2011) states that vinyl chloride levels of 1 µg/L are achievable using air stripping.

Small system compliance technologies for the removal of vinyl chloride in drinking water

include granular activated carbon (GAC), PTA, diffused aeration, multistage bubble aeration,

tray aeration and shallow tray aeration (U.S. EPA, 1998, 2009c). The PTA process is effective,

but the equipment is relatively expensive to build and maintain, and it may not be appropriate for

small water treatment utilities.

Vinyl chloride has been reported as a degradation product of the microbial reductive

dechlorination of chlorinated hydrocarbons such as tetrachloroethene and trichloroethene (IPCS,

1999; Bradley, 2000).

Vinyl chloride is primarily of concern as a potential contaminant from some older grades

of PVC pipes, mainly manufactured prior to 1977 (Flournoy et al., 1999; Carroll and Eckstein,

2001; Beardsley and Adams, 2003; MDNR, 2006).

7.1.1 Air stripping and PTA

Air stripping treatment technology is commonly used to reduce the concentration of

VOCs in drinking water (Cummins and Westrick, 1990; U.S. EPA, 1991; Dyksen, 2005). An air

stripping process brings water and air into contact, allowing the transfer of volatile contaminant

from the water to the air, as the driving force of the process is the contaminant concentration

gradient between the two phases.

A variety of configurations exist with respect to air stripping equipment; however, PTA

provides an optimum system for the removal of VOCs from water, as it allows for greater air to

water ratios compared with other aeration systems. In the PTA column, the contaminated water

flows downward by gravity over a bed of packing material, while the air is introduced into the

tower below the packed bed and flows countercurrent to the water flow. Several factors affect the

rate of stripping of the VOCs from water: the air to water ratio; the available area of mass

transfer; the hydraulic loading rate; the temperature of the water and air; and the physical and

chemical properties of the contaminant (AWWA, 1991; Crittenden et al., 2005; Dyksen, 2005).

As the PTA transfers VOCs from water to air, treatment of the stripping tower off-gas may be


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13

necessary to reduce the contaminant concentrations prior to discharge into the atmosphere

(Crittenden et al., 1988; Adams and Clark, 1991).

A common operating problem is the scaling and fouling of the packing material of the

column. The main causes of fouling are calcium carbonate or calcium sulphate scale, iron

oxidation and microbial growth. Methods to prevent the fouling of the column include pH

suppression of the PTA influent, the use of scale inhibitors or iron removal prior to the PTA

application (ESE, 1984; Dyksen, 2005). Algal growth can also be a problem in locations where

light could be introduced into the tower. Post-treatment processes, such as the use of a corrosion

inhibitor, may also be required to reduce the corrosive properties of the water as a result of

increased dissolved oxygen from the aeration process. Environmental conditions, such as water

temperature, may have an impact on the packed tower performance. Contact between the water

and the air in PTA column leads the air temperature typically to approach the water temperature.

The temperature influences both the Henry’s Law constant and the rate of mass transfer. These

parameters affect the size of the column and the efficiency of removal of the VOCs (Crittenden

et al., 2005).

A study using a full-scale PTA system indicated that an average influent vinyl chloride

concentration of 8.4 µg/L can be reduced to below 0.3 µg/L using an air to water ratio of 61, a

design hydraulic loading rate of 29.8 gpm/ft2 (20.1 kg/m

2/s), an air stripper length of 7.5 meters,

and a packed column diameter of 2.4 meters (Hand et al., 1988).

U.S. EPA pilot studies conducted at more than 30 water treatment sites showed that PTA

achieved > 99% VOC removals. As vinyl chloride is more easily removed by aeration than are

other VOCs included in the studies, the U.S. EPA concluded that PTA systems designed using

reasonable engineering practices could achieve 99.9% removal of vinyl chloride (U.S EPA,

2009c). Pilot-scale data have demonstrated removal efficiencies of 99.9% and 99.5% using air to

water ratios of 20 and 5, respectively. No information was provided on the influent

concentrations (ESE, 1984).

After an evaluation of the cost of PTA technology for the control of selected organic

compounds in drinking water, Adams and Clark (1991) indicated that the cost-effective PTA

design parameters for the reduction of vinyl chloride include an air to water ratio of 5 and a

packing depth of 6.9 m. Under these estimated conditions, a 99% reduction of vinyl chloride

could be achieved, from an influent level of 100 µg/L to a level of 1 µg/L in the finished water.

Spray aeration and air-lift pumping are identified as alternative air stripping treatment

technologies for the reduction of vinyl chloride in drinking water, achieving > 99.0% and 97.0%

reductions, respectively (U.S. EPA, 1985b).

7.1.2 Granular activated carbon

The U.S. EPA identified GAC as an effective technology for the removal of VOCs from

drinking water, with the exception of vinyl chloride. Study reports showed that the adsorption of

vinyl chloride by GAC is a sporadic and erratic process and that vinyl chloride cannot be

effectively removed (U.S. EPA, 1987a, 1987b; Hand et al., 1988 Lykins and Clark, 1994). A

carbon adsorption isotherm for vinyl chloride has not been reported in the literature.

A pilot-scale study reported an erratic pattern for the treatment of vinyl chloride by GAC

adsorption (U.S. EPA, 1987b). Data from the study demonstrated that a series of four 30-inch

(0.76 m) GAC columns was capable of reducing vinyl chloride concentrations of up to 19 µg/L

to a concentration below 0.5 µg/L in the finished water, achieving 810, 1250, 2760 and 2050 bed

volumes for an empty bed contact time of 6, 12, 19 and 25 minutes, respectively.


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14

Adams and Clark (1991) estimated cost-effective design parameters for liquid-phase

GAC treatment of VOCs, including vinyl chloride, in drinking water. The estimated carbon

usage rate to reduce an influent vinyl chloride concentration of 100 µg/L to a finished water

concentration of 1 µg/L was 2.94 lb/1000 gallons (0.35 kg/m3), with an empty bed contact time

of 30 minutes and a bed life of 28 days.

GAC adsorption with a combination of aeration technologies could be extremely

effective for producing water with low VOC concentrations in the finished water (Robeck and

Love, 1983; McKinnon and Dyksen, 1984). The aeration step reduces the organic load to the

adsorbent and may remove compounds competing for adsorption sites (Stenzel and Gupta,

1985). In addition, this step can significantly extend carbon bed life (Hess et al., 1981a;

McKinnon and Dyksen, 1984).

The U.S. EPA (1998) identified GAC as a small system compliance technology for the

removal of vinyl chloride in drinking water. GAC is the most widely used technology for small

systems due to the general ease of use, practicality and affordability. Generally, small systems

use closed GAC systems which have a higher treatment efficacy.

7.1.3 Ozonation and advanced oxidation processes

Ozonation and advanced oxidation processes (AOPs) have been reported to be effective

for the reduction of vinyl chloride concentrations in drinking water, although data from full-scale

systems were not available for these treatment methods (Lykins and Clark, 1994; Schwammlein

and Leitzke, 1995; Zhong et al., 2002). AOPs refer to the use of appropriate combinations of

ultraviolet (UV) light, chemical oxidants and catalysts to generate highly reactive radicals, such

as hydroxyl radicals, which are strong oxidants and react rapidly and non-selectively with

organic contaminants. Physical and chemical properties of the water to be treated, such as

alkalinity, pH, natural organic matter, iron and manganese, and turbidity, have a major impact on

AOPs, as they scavenge hydroxyl radicals or absorb UV light used to produce the radicals

(Crittenden et al., 2005).

In pilot plant ozone (O3) tests, removal efficiency for vinyl chloride in groundwater in the

range of 70–100% was observed with O3 doses of 2–6 mg/L. Concentrations in the influent and

in the finished water were not identified (Clark et al., 1988). Other pilot-scale tests conducted

with O3/hydrogen peroxide (H2O2), UV/ O3 and UV/ H2O2 showed that all three processes

achieved greater than 97% removal of vinyl chloride in groundwater under a variety of operating

conditions. The results demonstrated reduction of an influent concentration in the range of 4–

25 µg/L to a concentration below 0.5 µg/L (Schwammlein and Leitzke, 1995).

The performance of AOPs for the treatment of contaminated groundwater with

chlorinated ethenes, including vinyl chloride, has been reported in non-peer-reviewed paper. The

pilot-scale application of ozone/hydrogen peroxide treatment was reported to be effective for the

treatment of an influent vinyl chloride concentration of 900 µg/L to levels below 0.5 µg/L in the

finished water with an ozone dose of 32.2 mg/L (Bowman, 2003).

The formation of by-products, including disinfection by-products, from the oxidation

and/or advanced oxidation of vinyl chloride or other inorganic or organic compounds in the

source water should be considered when using these processes. The types and concentrations of

by-products formed will be dependent on the source water quality, concentrations of the oxidants

and the reaction contact time. Dowideit and von Sontag (1998) and von Gunten (2003) identified

hydroxymethylhydroperoxide, formyl chloride and formic peracid as the by-products formed

during ozonation of vinyl chloride in water. Another drawback of the use of AOPs such as


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15

ozone/hydrogen peroxide and ozone/ultraviolet is the formation of bromate in waters containing

bromide ion (Fronk et al., 1987; Crittenden et al., 2005). The presence of by-products may

require additional treatment following AOPs and/or process optimization to minimize by-product

formation.

7.1.4 Emerging technologies

New experimental technologies have been shown to have potential for removing VOCs,

including vinyl chloride, but there is not sufficient information available at present to fully

evaluate the technologies:

Catalytic hydrodehalogenation: Catalytic hydrodehalogenation processes (replacement of

halide by hydrogen), using hydrogen gas and palladium catalyst supported on alumina or

GAC, have been evaluated for the treatment of chlorinated ethenes in contaminated water

(Marques et al., 1994; Shreir and Reinhard, 1995). In a laboratory experiment using 0.5 g

of 0.5% palladium on alumina and 0.1 atm H2, vinyl chloride at an initial concentration of

1 mg/L in spiked tap water was completely hydrodehalogenated within 10 minutes at

room temperature. The presence of nitrite, nitrate and sulphate ions caused a minor

decrease in the rate of the hydrodehalogenation reaction. The presence of sodium

bisulphide resulted in deactivation of the palladium catalyst (Shreir and Reinhard, 1995).

Pervaporation: Although the use of membranes for the pervaporation extraction of VOCs

has been applied primarily in wastewater treatment, this technique also has been studied

for the removal of VOCs from groundwater (Jian and Pintauro, 1997; Uragami et al.,

2001; Peng et al., 2003). Pervaporation is a membrane process in which a liquid stream

containing VOCs is placed in contact with one side of an organophilic polymer

membrane while a vacuum or gas purge is applied to the other side. The contaminants in

the liquid stream adsorb into the membrane, diffuse through it and evaporate into the

vapour phase.

7.1.5 Distribution system materials: PVC/CPVC

In the polymerization process, some of the vinyl chloride monomers are retained in the

product matrix as a residue and may be released into the air or water.

The migration of vinyl chloride monomer from PVC pipes, mainly manufactured prior to

1977, was reported to be a possible source of vinyl chloride in drinking water (Flournoy et al.,

1999; Carroll and Eckstein, 2001; Beardsley and Adams, 2003; MDNR, 2006). A study

examining PVC pipes from the dead-end water distribution lines installed between 1960 and

1977 reported vinyl chloride levels in the range from non-detectable to 9.4 µg/L, the maximum

being 25 µg/L (MDL of 0.1 µg/L) (Beardsley and Adams, 2003). As stated in section 5.1.1,

plastic pipes and components used for potable water applications must now comply with

NSF/ANSI Standard 61 which ensures minimal leaching of vinyl chloride into drinking water

(CSA, 2009; NSF, 2012; NRCC, 2010).

Several studies have investigated the factors affecting the rate of leaching and the

accumulation of vinyl chloride from PVC and CPVC piping used in drinking water applications

(Al-Malack et al., 2000; Al-Malack and Sheikheldin, 2001; Al-Malack, 2004; Richardson and

Edwards, 2009; Walter et al., 2011). Static laboratory experiments conducted with PVC reactors

(PVC locally manufactured in Saudi Arabia) indicated that vinyl chloride at 2.5 µg/L

accumulated in extracted (double-distilled) water after 30 days of exposure to 45°C; vinyl

chloride at 2.3 µg/L accumulated in extracted water after 14 days of exposure to direct UV


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16

radiation at an intensity of 218 mW/cm2 and a temperature of 25°C (Al-Malack, 2004); vinyl

chloride at > 2.5 µg/L was detected in extracted water after 30 days of exposure to direct solar

radiation (Al-Malack and Sheikheldin, 2001); and vinyl chloride at concentrations up to 2.1 µg/L

was detected in both reactors with groundwater (total dissolved solids 2670 mg/L) and

chlorinated drinking water (total dissolved solids 160 mg/L) after 17 days of exposure to 45°C.

The MDL for all experiments was 0.6 µg/L.

Laboratory experiments compared the leaching rate and the accumulation of vinyl

chloride, in drinking water from static PVC and CPVC fragment/segment reactors and from in-

use consumer water lines (Richardson and Edwards, 2009; Walter et al., 2011). The pipes were

provided by different U.S. manufacturers and were certified to NSF International/American

National Standards Institute (NSF/ANSI) Standard 61 for potable water applications. A 2-year

laboratory study using static new schedule 40 PVC segment reactors filled with chlorinated tap

water reported vinyl chloride concentrations below the detection limit until day 63 (limit of

quantification [LOQ] of 0.095 µg/L). An equilibrium concentration of approximately 0.3 µg/L

was reported on day 715 (LOQ of 0.006 µg/L; Walter et al., 2011).

In a short-term (4 days) laboratory study, all new pipes (schedule 40 PVC, schedule 80

CPVC and SDR11 CPVC) provided by different manufacturers showed detectable levels of vinyl

chloride in chlorinated tap water in the range of 0.011–0.025 µg/L at day 4 of the experiments

(LOQ of 0.006 µg/L). The authors reported no statistically significant differences in vinyl

chloride levels between the types of piping (PVC vs. CPVC). However, variations in vinyl

chloride levels were seen between different pipe manufacturers (Walter et al., 2011).

In order to investigate the effect of pipe age on leaching rate, Richardson and Edwards

(2009) conducted laboratory experiments with new and aged PVC/CPVC segment reactors

(schedule 40 PVC, schedule 80 CPVC and schedule 80 PVC). Laboratory experiments were

conducted on new PVC/CPVC segment reactors with no biofilm or with biofilm artificially

grown for 11 months, both present and subsequently removed. Based on the graphical

representation of the experimental data, on day 7 of the experiment, reactors with artificially

grown biofilm had estimated vinyl chloride levels of 0.009 µg/L in the PVC reactors and

0.007 µg/L in the CPVC reactors. In the reactors where the biofilm was removed, vinyl chloride

levels were detected but not quantifiable in the PVC reactors and were estimated to be

0.009 µg/L in the CPVC reactors. In both new PVC and CPVC reactors, vinyl chloride levels

were > 0.014 µg/L and < 0.008 µg/L, respectively (limit of detection [LOD] of 0.0045 µg/L;

Richardson and Edwards, 2009).

Richardson and Edwards (2009) concluded that a faster accumulation of vinyl chloride

occurred in 15-year-old PVC segment reactors compared with 2-year-old PVC loop segment

reactors, regardless of whether biofilm was present or removed. In laboratory experiments

conducted with 2-year-old schedule 40 PVC loop segment reactors and chlorinated tap water,

vinyl chloride levels were approximately 0.0072 µg/L on day 3. By day 7 of the experiments,

vinyl chloride concentrations were in the range of 0.01–0.012 µg/L when the biofilm was intact

and 0.01–0.014 µg/L when the biofilm was removed. Experiments conducted with 15-year-old

schedule 80 PVC segment reactors filled with chlorinated tap water showed vinyl chloride levels

of 0.0057 µg/L (biofilm intact) and 0.0086 µg/L (biofilm removed) by the second hour. By day 7

of the experiments, vinyl chloride concentrations reached levels > 0.10 µg/L for reactors with

biofilm intact and > 0.12 µg/L for those with biofilm removed (LOD of 0.0045 µg/L; Richardson

and Edwards, 2009). According to the authors, the faster leaching rate for a 15-year-old pipe,

whose surface had a rust colour, may be caused by damage to the pipe structure. The authors also


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17

noted that PVC pipe segments with natural biofilm removed (2-year-old and 15-year-old PVC)

leached vinyl chloride at rates slightly higher than those with biofilm intact.

Long-term (2 years) laboratory experiments using schedule 40 PVC and schedule 80

CPVC fragment reactors (no biofilm) investigated the impact of temperature on the leaching rate

of vinyl chloride in the water. Based on the graphical representation of the experimental data,

vinyl chloride concentrations were below the detection limit in all PVC and CPVC reactors

incubated at 4°C. Vinyl chloride levels were estimated to be 0.1 to < 0.16 µg/L at 22°C, 0.07 to

< 0.12 µg/L at 37°C and > 0.1 µg/L at 52°C for PVC reactors; and < 0.05 µg/L at 37°C and 0.04

to < 0.06 µg/L at 52°C for CPVC reactors. Henry’s Law constants were applied to calculate the

vinyl chloride concentrations in the water at the different temperatures (Richardson and

Edwards, 2009).

In order to investigate the effect of mixed-species biofilm coverage on biotic reactors,

experiments were conducted with schedule 40 PVC and schedule 80 CPVC fragment reactors

with biofilm, with killed biofilm (soaked in formaldehyde), with scraped biofilm and without

biofilm. The biofilms were artificially grown on new pipe fragments and stored at 22°C for more

than 2 years. Richardson and Edwards (2009) reported quantifiable vinyl chloride levels in the

range of 0.124–0.158 µg/L (LOD of 0.045 µg/L) for all PVC reactors, regardless of whether

biofilm was present, killed or scraped. Vinyl chloride levels were below the detection limit for

all CPVC with the exception of the reactor with biofilm. In this case, the levels were above the

detection limit, but not quantifiable.

In summary, the results from static -pipe segment/fragment reactors indicated that the

quantity of vinyl chloride leached from newer PVC reactors is higher than that from CPVC

reactors in term of leaching rate and equilibrium concentrations (Richardson and Edwards,

2009).

In order to assess the vinyl chloride concentrations in tap water resulting from PVC and

CPVC pipes, field samples were collected from 15 consumer homes. Vinyl chloride at

concentrations in the range of 0.011–0.023 µg/L (LOQ of 0.006 µg/L) was detected in 3 of the

15 consumers’ tap water samples. These homes had small-diameter CPVC pipes (<1") and were

connected to chlorinated municipal water supplies (Walter et al., 2011). The age of two of the

pipes were established (6 and 21 years), whereas the third pipe’s age was unknown. Flushing of

the pipes did not result in any differences in vinyl chloride concentrations before or after flushing

in these homes. The study suggested that the chlorine residual in the water may contribute to

vinyl chloride accumulation in the distribution system via disinfection by-product reactions

(Walter et al., 2011). This fact is supported by laboratory experiments conducted with CPVC and

copper pipe reactors. CPVC reactors with chlorinated tap water accumulated higher levels of

vinyl chloride (levels not reported) than did reactors with dechlorinated water. Copper pipe

reactors, which eliminated vinyl chloride accumulation via leaching, showed detectable levels of

vinyl chloride in chlorinated water and not detectable levels of vinyl chloride in dechlorinated

water by the 101st hour (4 days). After 2 months of the experiments, all reactors with

dechlorinated water showed levels below the detectable level, whereas two of the triplicate

samples with chlorinated water showed detectable levels up to 0.01 µg/L (LOQ of 0.006 µg/L)

(Walter et al., 2011).

Another study reported no detectable levels of vinyl chloride in the raw water (MDL of

0.013 µg/L). However, average (and maximum) vinyl chloride concentrations of 0.04 µg/L

(0.48 µg/L) and 0.014 µg/L (0.25 µg/L) were reported in treated and distributed water,

respectively (Chung et al., 1997).


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18

Several studies reported the formation of chloroacetaldehyde (CAA) and chloroacetic

acid as a result of the reaction between the vinyl chloride migrating from the PVC pipes and the

chlorine residual in the water (Ando and Sayato, 1984; Wolf et al., 1987; IPCS, 1999).

7.2 Residential scale

It is not generally recommended that drinking water treatment devices be used to provide

additional treatment to municipally treated water. However, the migration of vinyl chloride

monomer from PVC pipes manufactured mainly prior to 1977 was reported to be a possible

source of vinyl chloride in drinking water distribution systems. In such cases, as well as where an

individual household obtains its drinking water from a private well, a private residential drinking

water treatment device may be an option for reducing vinyl chloride concentrations in drinking

water.

There is little information in the published literature regarding the effectiveness of GAC

treatment technology at the residential scale and no certified residential treatment devices are

currently available for the reduction of vinyl chloride in drinking water. However, one study

conducted on treatment devices using activated carbon filters demonstrated that they may be

effective for the reduction of vinyl chloride concentrations. The authors reported that countertop-

style carbon filters were capable of reducing levels of vinyl chloride monomer of approximately

13 µg/L to levels well below 2 µg/L (Carroll and Eckstein, 2001). Carbon filters may be installed

at the faucet (point of use) or at the location where water enters the home (point of entry). Point-

of-entry systems are preferred for VOCs, because they provide treated water for bathing and

laundry as well as for cooking and drinking. Some point-of-entry or point-of-use treatment

technologies such as activated carbon may remove vinyl chloride from the drinking water below

the MAC if two or more units are installed in series. No drinking water treatment device is

certified specifically for vinyl chloride removal at this time, as vinyl chloride is not currently

included in any ANSI/NSF treatment standard.

Before a treatment device is installed, the water should be tested to determine general

water chemistry and to verify the concentration of vinyl chloride. Periodic testing by an

accredited laboratory should be conducted on both the water entering the treatment device and

the finished water to verify that the treatment device is effective. Products that use adsorption

technology can lose removal capacity through usage and time and need to be maintained and/or

replaced. Consumers should verify the expected longevity of the adsorption media in their

treatment device as per the manufacturer's recommendations and service it when required.

Health Canada does not recommend specific brands of drinking water treatment devices,

but it strongly recommends that consumers use devices that have been certified by an accredited

certification body as meeting the appropriate NSF/ANSI drinking water treatment unit standards.

These standards have been designed to safeguard drinking water by helping to ensure the

material safety and performance of products that come into contact with drinking water.

Certification organizations provide assurance that a product conforms to applicable standards

and must be accredited by the Standards Council of Canada (SCC). In Canada, the following

organizations have been accredited by the SCC to certify drinking water devices and materials as

meeting NSF/ANSI standards (SCC, 2011).

CSA International (www.csa-international.org);

NSF International (www.nsf.org);

Water Quality Association (www.wqa.org);

Underwriters Laboratories Inc. (www.ul.com);


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19

Quality Auditing Institute (www.qai.org); and

International Association of Plumbing & Mechanical Officials (www.iapmo.org).

An up-to-date list of accredited certification organizations can be obtained from the SCC

(www.scc.ca).

As noted previously, low levels of vinyl chloride may leach from some PVC/CPVC pipes

used in drinking water systems and is best controlled by specification of material quality. The

NPC requires that all plastic pipes used for cold water applications for distribution system and

premise plumbing pipes and components (i.e., fittings) meet the CSA standard for plastic pipes.

The standard requires that PVC and CPVC pipes and components (e.g., tubing and fittings), used

for drinking water applications, comply with the requirements of NSF/ANSI Standard 61 (CSA,

2009). NSF/ANSI Standard 61 (Drinking Water System Components—Health Effects) ensures

that materials meet health-based leaching requirements and are safe for use in potable water

applications. This standard evaluates PVC and CPVC products and materials for the

concentration of residual vinyl chloride monomer in the product wall. Products and materials

must contain 3.2 mg/kg or less residual vinyl chloride monomer in the product wall (equivalent

to 0.2 µg/L or less in the drinking water) in order to be certified to NSF/ANSI Standard 61

(NSF/ANSI, 2012).

8.0 Kinetics and metabolism 8.1 Absorption

8.1.1 Experimental animals

In rats, vinyl chloride is readily absorbed via oral and inhalation routes of exposure and is

rapidly distributed throughout the body. After gastric intubation of male Wistar rats with 10 mL

of aqueous solutions containing vinyl chloride at concentrations of 2.26–2.82 mg/mL (total dose

22.6–28.2 mg/animal), peak blood concentrations (6 to > 40 µg/mL) were found in less than

10 minutes, and absorption was almost complete (Withey, 1976; Feron et al., 1981). One dose of

450 mg/kg body weight (bw) administered orally to rats resulted in 98.7% absorption from the

gastrointestinal tract (Green and Hathway, 1977).

Dermal absorption of vinyl chloride gas is not likely to be significant, as only 0.031%

and 0.023% of the total vinyl chloride doses (7000 ppm and 800 ppm, respectively) were

absorbed by male Rhesus monkeys, and the majority of the dose was exhaled (Hefner et al.,

1975a).

8.1.2 Humans

Inhalation of vinyl chloride at concentrations of 7.5, 15, 30 and 60 mg/m3 for six hours

resulted in rapid pulmonary absorption and retention of 40% in five young, healthy adult males

voluntarily exposed, independent of the concentration (Krajewski et al., 1980).

8.2 Metabolism

The metabolism of vinyl chloride has been quantitatively estimated in humans from gas

uptake experiments whereby after initial absorption of vinyl chloride, continued absorption is

mainly attributed to metabolism. When exposing young men to vinyl chloride at concentrations

of 7.5, 15, 30 and 60 mg/m3 by gas mask for six hours, Krajewski et al. (1980) reported that the

retention of vinyl chloride was found to be independent of the inhaled concentration and did not


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20

change with increasing vinyl chloride concentrations, suggesting that exposure to vinyl chloride

up to 60 mg/m3 did not cause saturation of the major metabolic pathway.

The fate of vinyl chloride in the animals appears to be dose dependent (Watanabe and

Gehring, 1976), which is primarily due to the linear kinetics of the metabolic pathway for vinyl

chloride at low doses. The metabolism of vinyl chloride has been shown to follow Michaelis-

Menten kinetics in rats, with enzyme saturation occurring following exposure to approximately

100 ppm in air or between 1 and 100 mg/kg bw/day for a single gavage dose (Hefner et al.

1975b; Watanabe et al. 1976a).

The vinyl chloride metabolic pathway occurs through mixed-function oxidase

cytochrome P450 2E1 (CYP2E1) both in vitro, with cell isolates of the microsomal fraction (S9)

from rats (Kappus et al., 1976; Guengerich and Shimada, 1991; el Ghissassi et al., 1998) and

humans (Guengerich et al., 1991) and with the human B-lymphoblastoid cell line (Chiang et al.,

1997), and in vivo, with rats (Watanabe et al., 1976a, 1976b) and Rhesus monkeys (Buchter et

al., 1980). Liver toxicity (vacuolization of the centrilobular parenchyma) increases in parallel

with P450 liver content in rats after vinyl chloride inhalation exposure to 50 000 ppm for 6 hours

(Reynolds et al., 1975).

Inhibition of vinyl chloride metabolism in rat and human microsomes was observed when

vinyl chloride exposure occurred in the presence of diethyldithiocarbamate, a CYP2E1 selective

inhibitor (Guengerich et al., 1991; el Ghissassi et al., 1998). Pretreatment of Sprague-Dawley

rats with a general mixed-function oxidase blocker (SKF-525A) impeded the metabolism of

inhaled vinyl chloride at a concentration of 1000 ppm (Hefner et al., 1975b).

Enzymatic transformation of vinyl chloride for excretion results in the generation of polar

intermediates (Antweiler, 1976; Kappus et al., 1976; Rannug et al., 1976). The two major

metabolites of vinyl chloride in the liver are the highly reactive and short-lived chloroethylene

oxide (CEO) and CAA (Whysner et al., 1996; el Ghissassi et al., 1998), a highly reactive α-

halocarbonyl compound which results from a rapid rearrangement of CEO (Pessayre et al.; 1979;

Whysner et al., 1996; el Ghissassi et al., 1998). These two metabolites are detoxified mainly

through glutathione (GSH) conjugation (Leibman, 1977; Tarkowski et al., 1980; Jedrychowski et

al., 1985) which is supported by the observation of decreased non-protein sulfhydryl

concentrations when exposed to high concentrations of vinyl chloride (Tarkowski et al., 1980;

Jedrychowski et al., 1985), and by the excretion of GSH-conjugated metabolites in the urine of

rats following exposure to vinyl chloride (Hefner et al., 1975b; Watanabe et al., 1976c). CAA

may also combine directly or enzymatically with GSH by way of glutathione transferase (GST)

to form S-formylmethylglutathione. S-formylmethylglutathione can act directly with GSH-

derived cysteine to form N-acetyl-S-(2-hydroxyethyl)cysteine which is another major urinary

metabolite of vinyl chloride (Green and Hathway, 1975). The GSH conjugates are then

hydrolysed, resulting in excretion of cysteine conjugates in the urine (Hefner et al., 1975b). The

two major metabolites identified in the urine of rats following exposure to vinyl chloride are N-

acetyl-S-(2-hydroxyethyl)cysteine and thiodiglycolic acid (Watanabe et al., 1976b).

8.3 Distribution and excretion

Vinyl chloride is distributed rapidly throughout the body, but poorly retained due to rapid

metabolism and elimination (OEHHA, 2000; ATSDR, 2006).

In rats exposed to 4.5–70 ppm 14

C-labelled vinyl chloride for five hours, vinyl chloride

was found to bind in the largest proportion in the liver, followed by the small intestine, kidney,

lung and spleen; this organ distribution is supported by the lipophilicity of vinyl chloride, as


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21

indicated by its low octanol:water partition coefficient of 1.62 (U.S. EPA, 2000a). Monkeys

acutely exposed by the skin to 14

C-labelled vinyl chloride gas also had detectable 14

C activity in

the bile, liver and kidney, however, no appreciable amount of activity was detected in other

tissues (Hefner et al., 1975a; Bolt et al., 1980).

In an experiment in which rats were given single oral doses (by gavage) of 0.05, 1.0, 20.0

or 100 mg/kg bw of 14

C-labelled vinyl chloride dissolved in corn oil, the percentage of the dose

exhaled within 72 hours as unchanged vinyl chloride was 1.4%, 2.1%, 41.4 and 66.6%,

respectively. Excretion in urine was 68.3%, 59.3%, 22.6 and 10.8%, respectively. 14

CO2 in

expired air accounted for 9.0%, 13.3%, 4.8% and 2.5%, respectively. A proportion of 0.47–

2.39% was unabsorbed and excreted unchanged in the faeces. The liver was found to retain the

maximum percentage of activity at all dose levels, 3–5 times the percentage found in muscle,

lungs or fat (Watanabe and Gehring, 1976).

Alderley Park rats (Wistar-derived strain) exposed to vinyl chloride at 1–450 mg/kg bw

pulmonarily excreted unchanged vinyl chloride after 3–4 hours, whereas polar metabolites and

labelled carbon dioxide continued to be excreted for 3 days (Green and Hathway, 1977).

When Sprague-Dawley rats were exposed to > 100 ppm (260 mg/m3) vinyl chloride in air

for 5 hours, 69% of the absorbed dose was excreted as metabolites within 24 hours in urine via

the kidney (Watanabe et al., 1976b; OEHHA, 2000). An additional 1.7% was found in the urine

24–48 hours later (Bolt et al., 1976). The half-life for urinary excretion in rats was about 4 hours.

The blood concentration fell rapidly after removal of vinyl chloride from the air (Withey, 1976).

Intravenous injection of vinyl chloride (250 µg of 14

C-labelled vinyl chloride per kg in N-

(β-hydroxyethyl) lactamide) was reportedly almost entirely exhaled (99%) after 1 hour by rats

(Green and Hathway, 1975).

Deoxyribonucleic acid (DNA) adducts were found in various tissues (testis, kidney,

spleen, lung, liver, lymphocytes) after exposing rats to 500 ppm vinyl chloride in air, suggesting

the migration of CEO via the bloodstream after liver metabolism (Guichard et al., 1996; Barbin,

1999). No ethenoguanine or 7-(oxoethyl)-guanine adducts were found in brains of rats exposed

to 1100 ppm vinyl chloride for 4 weeks (Morinello et al., 2002a). However, in this same study,

an increase of adducts in weanling rats was found (Morinello et al., 2002a).

Regardless of route of administration, as the dose of vinyl chloride increases, so does the

proportion of the dose (unmetabolized) that is exhaled; however, the proportion of the dose that

is excreted in the urine and faeces decreases with increasing dose (Green and Hathway, 1975;

Hopkins, 1979).

8.4 PBPK modeling

Several PBPK models have been developed for vinyl chloride. Clewell et al. (1995)

developed a PBPK model to refine the vinyl chloride risk calculation for animal to human

extrapolations based on pharmacokinetic information. To illustrate the pharmacokinetics of vinyl

chloride, four compartments were necessary for the model: liver, fat, and highly and poorly

vascularized tissues, with the liver being the site of metabolism and the target tissue in which

angiosarcoma of the liver (ASL) arises (Clewell et al., 1995). Further biotransformation of CEO,

resulting in carbon dioxide generation, glutathione depletion and binding of reactive metabolic

products to macromolecules in the liver, was also included in the model. The risk estimate for

vinyl chloride exposure was found to be consistent across species, routes and media of exposure,

showing agreement between the results and risk evaluation methods.


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22

Clewell et al. (2001, 2004) further refined their PBPK model to include the glutathione

dynamic and age extrapolations, based on CYP2E1 enzyme maturation and body weight–

clearance capacity; the refined model also takes into account each life stage with cumulative

exposure to 1 µg/kg bw per day over a lifetime. Blood concentrations of the parent compound

were found to be the highest very early in life (< 6 months old) and then decrease in early

childhood. The plateau reached in adulthood can be explained by rapid maturation of CYP2E1

after 6 months of age and changes in body weight–clearance capacity (Clewell et al., 2004).

Other PBPK models for vinyl chloride include those by Gentry et al. (2003), Chiu and

White (2006) and Yoon et al. (2007). The Gentry et al. (2003) model examines differences in

blood and tissue dose metrics between a mother and foetus (human) during pregnancy and

lactation. This model adds fetal liver, fetal blood and other fetal tissue compartments to the adult

model to account for transfers through the placenta and breast milk, as well as differences

between adult and fetal enzyme activity. The vinyl chloride concentrations in fetal blood were

predicted to be similar to concentrations in the mother’s blood during gestation, however, during

lactation, blood concentrations in the neonate were predicted to be much lower. Concentrations

of vinyl chloride and CEO in the liver were not predicted. Owing to the lack of a developed

CYP2E1 enzyme system, Gentry et al. (2003) concluded that fetal exposure to reactive

metabolites of vinyl chloride is expected to be negligible. However, there is some evidence that

transplacental exposure can result in carcinogenicity in rat studies, and the half-life of CEO may

be long enough for this reactive metabolite to cross the placenta after being generated in

maternal tissues (Rice, 1981). The Chiu and White (2006) human PBPK model incorporates

fewer parameters and assumes that all vinyl chloride metabolism occurs in the liver via first-

order kinetics. This model was found to duplicate the Clewell et al. (2001) model for

extrapolation between oral and inhalation exposure to vinyl chloride; however, as it assumes

first-order kinetics for metabolism, it is appropriate for use only in the dose range in which

metabolism is approximately linear. A model by Yoon et al. (2007), validated in Sprague-

Dawley rats, considered the effect of extrahepatic CYP2E1 on PBPK modeling results. The

results of the modeling indicated that extrahepatic CYP2E1 metabolism did not contribute

significantly to the results considering only liver metabolism, indicating that PBPK models only

considering liver metabolism are appropriate for the risk assessment of vinyl chloride.

Health Canada (2011) developed a PBPK model based on the one developed by Clewell

et al. (2001, 2004) to facilitate animal to human and high dose to low dose extrapolations for

vinyl chloride. The model was updated to include a dermal component so that it could be used to

estimate the contribution of showering and bathing to vinyl chloride exposure. The model was

validated using pharmacokinetic data from animals (Feron et al., 1981; Til et al., 1983) and

humans (Buchter et al., 1978) exposed to vinyl chloride. Non-cancer effects (liver toxicity) and

tumour progression (DNA adducts, mutations) have been shown to result from CEO generation;

therefore, the appropriate dose metric with which to estimate cancer and non-cancer risks

corresponds to the quantity of vinyl chloride metabolites produced divided by the liver volume.

Data from both Feron et al. (1981) and Til et al. (1991) were used for PBPK modeling by

Health Canada. The external doses from these studies were inputted into the rat PBPK model to

determine the cumulative lifetime internal dose of vinyl chloride metabolites generated per litre

of liver for several liver tumour endpoints in both male and female rats. During the modeling,

vinyl chloride oral uptake was designated as zero-order (independent of concentration) and

spread out over a 24-hr period; this ensured that saturation of the metabolic pathways was

avoided, thus generating a maximum value of the dose metric which is conservative with respect


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23

to what may actually occur during an oral dose. This approach, coupled with the use of the same

liver metabolic processes for both inhalation and oral inputs, increases the confidence in dose

metrics derived from oral inputs. It also addresses concerns of reduced confidence in dose

metrics derived from oral studies compared to those derived from inhalation studies (as indicated

experimental data). Using the multistage cancer model from the U.S. EPA’s benchmark dose

(BMD) software, BMDS (U.S. EPA, 2010), the internal concentrations of vinyl chloride

metabolites associated with an excess lifetime cancer risk of 10−4

, 10−5

and 10−6

in male and

female rats were estimated for several cancer endpoints in order to determine the most

appropriate point of departure (POD) for use in the human PBPK model. The cumulative lifetime

internal dose of vinyl chloride metabolites associated with combined liver tumours (neoplastic

nodules, hepatocellular carcinoma [HCC] and ASL) was determined as the most appropriate

POD to use in the human PBPK model to estimate the external human doses associated with

each risk level for a lifetime (70 years) exposure. The external human doses generated by the

model represent the levels in drinking water that would be associated with an excess lifetime

cancer risk in humans of 10−4

, 10−5

and 10−6

, when daily exposure to drinking water occurs

through ingestion (1.5 L-eq/day) as well as through inhalation (0.4 L-eq/day) and dermal (1.9 L-

eq/day) exposures from a 30-minute bathing scenario.

The estimated L-eq contribution from dermal exposure likely represents an over estimate

since the PBPK model accounts for exposure to both the liquid and gas phases of vinyl chloride

during a bathing event. Based on the physical/chemical properties of vinyl chloride and human

physiological characteristics, the PBPK model estimated an inhalation absorption of 33%; a

dermal absorption of 94% was estimated for the liquid phase (that is water containing solubilised

vinyl chloride) which represents the majority of the L-eqs for the dermal route and the gas phase

was determined as contributing a negligible amount of L-eqs given its very low absorption by the

skin. This is a conservative approach used in the absence of published data on the proportion of

solubilised vinyl chloride that could be present during showering or bathing; Health Canada

determined that this conservative approach is appropriate to estimate the L-eq contribution from

dermal exposure.

9.0 Health effects 9.1 Effects in humans

9.1.1 Acute effects

Vinyl chloride is a narcotic agent, and loss of consciousness can occur from exposure to

high concentrations (25 000 mg/m3). Acute exposure to high concentrations in air also causes

central nervous system depression, with symptoms of dizziness, light-headedness, nausea,

headache, irritability, poor memory, tingling sensations, weight loss, irritation of the respiratory

tract and chronic bronchitis (IARC, 2008). Autopsies of several vinyl chloride workers who died

following exposure to high levels revealed congestion of the liver, spleen and kidney (Cook et

al., 1971).

9.1.2 Chronic effects and cancer epidemiology

The association of vinyl chloride with the risk of death from liver angiosarcoma (ASL;

cancer of the liver blood vessels) reached public attention after the discovery of three cases in a

vinyl chloride plant (Creech and Johnson, 1974). Tumours of the respiratory tract, digestive

system, cardiovascular system and other sites from vinyl chloride exposure have been reported in


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24

a few controversial studies; however, the risk of ASL has been demonstrated by many

investigators to increase with the exposure length and intensity, the latency period, the year of

employment (before 1970) and age at first exposure (Simonato et al., 1991; Mundt et al., 2000;

Wong et al., 2002; Bosetti et al., 2003; Lewis et al., 2003). Other cancers, such as brain and lung

cancer, lymphoma and HCC, have been sparsely observed (Monson et al., 1975; Waxweiler et

al., 1976; Pirastu et al., 1990; Simonato et al., 1991; Wong et al., 1991) and their causal

relationship with vinyl chloride remains controversial.

In the 1970s, the International Agency for Research on Cancer (IARC) coordinated a

European multicentre study within Italy, Norway, Sweden and the United Kingdom with 14 351

individuals from 19 factories to investigate the relationship between exposure to vinyl chloride

and liver cancer as well as cancer risks for sites other than the liver. IARC (1979) concluded that

vinyl chloride could be associated with HCC, brain tumours, lung tumours and malignancies of

lymphatic and haematopoietic tissues. The data, analysed by Simonato et al. (1991), revealed a

nearly 3-fold increase in liver cancer deaths: 24 observed compared with 8.4 expected

(standardized mortality ratio [SMR] = 286; 95% confidence interval [CI] = 186–425). The

excess deaths from liver cancer were clearly associated with the elapsed time since the first

exposure, duration of employment and quantitative exposure scenarios based on job titles

(ranked level: ≤ 50, 50–499, ≥ 500 ppm; and cumulative estimates: 0–1999, 2000–5999, 6000–

9999, ≥ 10 000 ppm-years). No statistically significant excess mortality was reported for the

cancers at sites other than the liver due to exposure to vinyl chloride. A further analysis by Ward

et al. (2001) followed up on an additional 8 years of mortality and cancer incidence and reported

that mortality from all causes was lower than expected, whereas cancer mortality was close to

expected. A total of 53 deaths from primary liver cancer (SMR = 2.40; 95% CI = 1.80-3.14) and

18 cases of liver cancer were reported which included 37 angiosarcomas (ASL), 10 HCCs, and

24 other liver cancers; a clear exposure response relationship was reported for all liver cancers,

ASL, and HCC. Bosetti et al. (2003) confirmed the relationship between liver cancer and vinyl

chloride exposure, however, showed that the increasing trend for HCC was appreciably less

pronounced than for ASL, and that the relative risk for HCC was statistically significant only in

the highest category of cumulative exposure. Again, no association was found with other cancer

types.

The North American multicentre cohort of vinyl chloride workers has been followed by

various investigators, with a focus on the plants in Calvert City and Louisville, Kentucky

(Creech and Johnson, 1974; Monson et al., 1975; Waxweiler et al., 1976; Lewis and Rempala,

2003; Lewis et al., 2003). Monson et al. (1975) were the first to find increased deaths from all

cancers, particularly of the liver, biliary tract (SMR = 11.0) and brain (SMR = 4.2), but also of

the lung (SMR = 1.6) and lymphatic tissue (SMR = 1.5). In a follow-up based on cumulative

estimates ranking workers within exposure groups ≤ 100, 100–400, 400–1000 and ≥ 1000 ppm

multiplied by the number of months worked, Lewis and Rempala (2003) confirmed the high

occurrence of liver and brain cancer among workers from the Louisville plant. Deaths from total

liver cancer and ASL were strongly related to vinyl chloride exposure intensity (P < 0.001).

Wong et al. (1991) analysed data, including from the Louisville plant, for 10 173 men exposed to

vinyl chloride for at least 1 year before 1973 at 37 plants in the United States. This represents the

largest group of vinyl chloride workers in North America. The study confirmed that workers

exposed to vinyl chloride experienced a significant excess mortality due to ASL (15 deaths),

cancer of the liver (unspecified type) and biliary tract (SMR = 641) and cancer of the brain and

central nervous system (23 deaths compared with 12.8 expected; SMR = 180). However, half of


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25

the cases of brain cancer came from two plants that were manufacturing only PVC. Only the

deaths from liver cancer showed increased occurrence by length of exposure and by latency

period since first exposure and decreasing trends by age at first exposure. The study did not find

any excess in respiratory cancer or lymphatic and haematopoietic cancers. Lewis et al. (2003)

separated the Louisville cases from the large U.S. vinyl chloride workers cohort and found that

liver cancer mortality remained high compared to the total U.S. cohort (SMR = 400 and 359,

respectively), but brain cancer deaths increased dramatically (SMR = 229 and 142, respectively).

Another follow-up to December 31, 1995, by Mundt et al. (2000) added the number of deaths

after a latency period of 20–50 years. Again, the cancer risk was higher for workers employed

earlier (SMR = 499 before 1950) and longer (SMR = 434 for 30 years or more). Liver and biliary

tract cancer deaths were still in excess, although slightly decreased since the 1980s; brain cancer

deaths were no longer different from the controls.

Data from nine United Kingdom vinyl chloride plants involving 7717 workers employed

between 1940 and 1974 found only two cases of ASL (Fox and Collier, 1977). A follow-up

including 5498 workers from this study added 10 years of latency and discerned exposure

categories based on job titles and length of employment (Jones et al., 1988). A significant

increase of deaths from liver cancer (SMR = 567) was reported among autoclave workers with

the highest vinyl chloride exposure; out of 11 observed deaths, 2 were expected, and 7 of the 11

deaths were largely attributable to ASL (SMR = 1842).

Pirastu et al. (1990) conducted a mortality study on 5946 vinyl chloride and PVC workers

from nine Italian plants. Analysis of the data from 253 deaths (death certificates, clinical and

pathological information) confirmed the carcinogenic action of vinyl chloride, with 14 liver

cancers, but no other cancers were reported in any of the other suggested target organs (i.e., lung,

lymphopoietic tissues, brain). The cancers were observed in various job titles that exposed

workers to different concentrations; however, these levels were not specified by the authors. Of

the 14 liver cancers, seven were ASL and two were HCC. Later, Pirastu et al. (2003) updated the

mortality and occupational history for an Italian plant in Porto Marghera until 1999. Cumulative

exposures were determined on the basis of job- and time-specific exposure estimates, and

classified into six exposure categories (0–735, 735–2379, 2379–5188, 5188–7531 and 7531–

9400 ppm–years) with employment as an autoclave worker (ever/never) also considered in the

analyses. Clinical and pathological data which gave the best diagnosis were used to identify

cases of liver angiosarcoma and hepatocellular carcinoma. With regional rates as a reference,

mortality in the cohort for all causes (SMR, 0.75; 90% CI, 0.68–0.83) and all cancers (SMR,

0.94; 90% CI, 0.81–1.09) was lower than expected. For all causes, the analysis by time since

leaving employment and adjusted for latency showed that the SMR in the first year after leaving

employment was 2.76 (90% CI, 1.94–3.91). Mortality rates for liver angiosarcoma (six cases)

increased with latency and cumulative exposure, however, no cases were associated with

duration of employment of less than 12 years, latency of less than 10 years or cumulative

exposure of less than 2379 ppm–years. Mortality rates for hepatocellular carcinoma (12 cases)

and liver cirrhosis (20 cases) showed a similar pattern. For this cohort, Mastrangelo et al. (2003,

2008) confirmed that an increase in deaths from liver cancer was associated with vinyl chloride

inhalation exposure.

Boffetta et al. (2003) analysed the data from six studies of the U.S. and European cohorts.

They found a low incremental average SMR from the studies for liver cancer other than ASL

(SMR = 1.35; 95% CI = 1.04–1.77). Of the six studies, only four were still positive for liver

cancer when ASL was excluded. Moreover, no association between brain cancer or lymphatic


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26

and haematopoietic neoplasms and vinyl chloride exposure was found, contrary to the findings of

Theriault and Allard (1981) and Wong et al. (1991).

Laplanche et al. (1992) analysed data from a French prospective cohort study by the

French National Institute of Health and Medical Research (INSERM) representing 1100 exposed

and 1100 unexposed subjects. Diseases of the respiratory system did not differ between the two

groups (relative risk [RR] = 1.1; 95% CI = 0.7–1.8); however, 3 cases of ASL and 14 cases of

Raynaud’s disease were found among the exposed group, and 1 case of Raynaud’s disease was

noted among non-exposed subjects.

Data from male workers employed for at least 1 year during the period 1950–1992 in

Taiwan were analysed by Wong et al. (2002). Being employed when younger than 30 years of

age increased the risk of death (SMR = 2.24). Those employed before 1970 were 5 times more

likely to develop liver cancer (unspecified type) than the general population. No increased risk

was found for longer employment duration or for development of brain tumours. The study

confirmed an increased mortality from cancer (SMR = 1.30), with the liver as the main target

organ (SMR = 1.78).

Based on five registry sources from the United Kingdom, including the national cancer

registry and death certificates, no non-occupational cases of ASL among residents within 10 km

of a vinyl chloride industrial site were found (Elliott and Kleinschmidt, 1997). Of the 52 cases of

ASL registered during 1979–1986, only 11 were within 10 km of a vinyl chloride industrial site.

From those 11 cases, 10 had been employed in a vinyl chloride plant, whereas the remaining case

was thought to be a misclassified ASL diagnosis.

Infante et al. (2009) reported two cases of ASL in hairdressers and barbers who used

hairsprays containing vinyl chloride as a propellant over a period of 4 to 5 years between 1966

and 1973. The peak exposure for Case 1 (hairdresser) was estimated to range from 129 to 1234

ppm, with a 8-hour time weighted- average (TWA) vinyl chloride exposure estimated to have

ranged from 70 to 1037 ppm (median TWA estimated at 228 ppm); estimates for Case 1 were

dependant on the products used (% vinyl chloride varied based on product used), the length of

time of spraying the product, and the number of estimated air exchanges per hour. For Case 2

(barber), atmospheric levels of vinyl chloride from a 22 second spray in a room with 4 air

exchanges were estimated to range from 129 ppm at the outset to approximately 40 ppm after 40

minutes had elapsed, with an average exposure of 70 ppm over the 40 minute period. The authors

concluded that to their knowledge this represents the first literature reports of ASL cases

identified among hairdressers and barbers who used hair sprays containing vinyl chloride as a

propellant.

9.1.3 Non-cancer endpoint epidemiology

The liver remains the primary target organ of vinyl chloride for non-cancer endpoints

(U.S. EPA, 2000b). Occupational exposure to high levels of vinyl chloride (2400 ppm-month) is

an independent risk factor for the development of liver fibrosis (cirrhosis) (Hsiaos et al., 2004).

Impaired liver functions with evidence of porphyria, liver enlargement, hepatocyte hypertrophy

and fibrosis were observed by many authors in workers exposed to vinyl chloride for a variable,

but considerable, amount of time (Gedigk et al., 1975; Lilis et al., 1975; Popper and Thomas,

1975; Berk et al., 1976; Doss et al., 1984).

Vinyl chloride tank cleaners were exposed to vinyl chloride at concentrations of hundreds

of parts per million, producing a wide range of effects, including Raynaud-like syndrome,

acroosteolysis (bone resorption in the fingers and toes), thrombocytopenia, scleroderma-like


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27

dermatitis, thyroid insufficiency, damage to the liver (steatohepatitis), spleen and lungs, as well

as functional disturbances of the central nervous system (Cook et al., 1971; Lilis et al., 1975;

ECETOC, 1988; U.S. EPA, 2000b). An effect of vinyl chloride on coronary heart disease was

not found, but a direct relationship between vinyl chloride exposure and development of arterial

hypertension was observed (Kotseva, 1996). Ho et al. (1991) revealed an increase of glutamic

pyruvic transaminase concentrations before and after the occurrence of liver dysfunction in

workers exposed to vinyl chloride levels ranging from 1 to 21 ppm.

9.1.4 Mutagenicity/genotoxicity

Accidental and occupational exposures to vinyl chloride and its metabolites have been

associated with chromosomal aberrations and gene mutations in humans. A single acute

exposure to vinyl chloride in air after an environmental accident in Germany led to slight

increases in chromatid breaks, acentric fragments, dicentrics and translocations in peripheral

blood lymphocytes in 27 exposed individuals compared with those unexposed (Hüttner and

Nikolova, 1998). However, the exposure did not produce any significant chromosomal

abnormalities in the HPRT locus of lymphocytes, measured immediately or 2 years later,

compared with 29 non-exposed individuals (Becker et al., 2001).

Mutations of both pro-carcinogenic genes p53 (A:T mis-sense mutations) and ras, leading

to the expression of altered p53 and p21ras

proteins (Trivers et al., 1995), were detected in tumour

samples from workers who developed ASL and HCC after being occupationally exposed to vinyl

chloride in the United States, France and Taiwan (Marion et al., 1991; De Vivo et al., 1994;

Weihrauch et al., 2000, 2001, 2002). A dose–response relationship was observed between vinyl

chloride exposure and the mutation of p53 and ras (Smith et al., 1998). Further, chronic

occupational exposure to 1.3–16 ppm vinyl chloride resulted in sister chromatid exchange and

chromosomal aberrations such as DNA breaks in a group of 52 workers (Sinués et al., 1991) and

in another group of 57 workers exposed to an average of 2 ppm vinyl chloride with occasional

excursions of up to 1000 ppm (Purchase et al., 1985).

Gene polymorphism has reportedly affected vinyl chloride workers in Taiwan and China.

An increase in sister chromatid exchanges and micronuclei was observed in exposed workers and

in individuals expressing specific alleles. For example, the homozygous individuals bearing the

c2c2 allele of the CYP2E1 gene (P < 0.05) or the variant allele Arg399Gln of the DNA repair

gene XRCC1 (P < 0.05) had more micronuclei (Wong et al., 2003; Ji et al., 2010). The variant

allele c2c2 of CYP2E1 reportedly metabolizes vinyl chloride at a higher rate, thus generating

more CEO per time unit (Wong et al., 2003). A significant increase in liver fibrosis incidence

was reported among CYP2E1 c2c2 allele carriers in a group of 320 vinyl chloride workers

employed in five different vinyl chloride factories in Taiwan (Hsieh et al., 2007). Fucic et al.

(1996) demonstrated that the chromosomal damage was reversible after occupational exposure

levels dropped below 1 ppm in vinyl chloride plants. However, sister chromatid exchanges were

persistent and detected up to 10 years after the last occupational exposure to levels higher than 1

ppm (Fucic et al., 1996).

Chiang et al. (1997) reported that 16 µM of CEO or CAA for 24 hours induced similar

mutation frequencies of the HPRT locus in human B-lymphocytes, but that CAA was more

cytotoxic (cell proliferation assay). When plotted as a function of relative survival, CEO induced

mutations at a rate similar to that of vinyl chloride, but 6 times higher than that of CAA. The

authors concluded that CEO is responsible for larger deletions and for most of the mutations

induced by vinyl chloride exposure (Chiang et al., 1997).


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28

9.1.5 Reproductive and developmental toxicity

No adverse reproductive effects were reported in workers exposed to vinyl chloride

(Hemminki et al., 1984), although an increase in total birth malformations in populations

employed in the vinyl chloride industry has been suggested by a few investigators (Infante et al.,

1976; Theriault et al., 1983). An association between parental occupational exposure to vinyl

chloride and fetal loss has also been suggested (RR = 1.8) (Infante et al., 1976; Waxweiler et al.,

1976), but exposures were not measured.

Theriault et al. (1983) investigated the incidence of birth defects in infants born between

1966 and 1979 to residents of Shawinigan, Quebec, a town where a vinyl chloride

polymerization plant had been in operation since 1943. The incidence of birth defects (observed

159 vs. expected 107) was significantly higher in Shawinigan than in any or all of the matched

control towns with no potential exposure to vinyl chloride. The incidence rate peaked in March

and was lowest in September, which corresponded to variation in atmospheric levels of vinyl

chloride at the time of the first 3 months of pregnancy (vinyl chloride monomer was not detected

in air samples taken between December and February). No such variations were observed in the

control communities. However, there was no excess of stillbirths in Shawinigan. As several other

industries emitted pollutants into the atmosphere in Shawinigan, these observations remain

inconclusive.

9.1.6 Children’s sensitivity

Evidence from animal studies suggests that very young children may be particularly

sensitive to the carcinogenic effects of vinyl chloride (see Section 9.2.6). The rate of cell division

in the brain, liver and kidney is much higher in the first 2 years of life than in later childhood,

making the liver more sensitive to DNA adduction and hepatocarcinogenesis from vinyl chloride

exposure during this time (Ginsberg, 2003). A second growth peak for the liver may occur

around the age of 6, indicating that children this age may also be sensitive to vinyl chloride

(Ginsberg, 2003).

9.2 Effects in experimental animals and in vitro

9.2.1 Acute effects

Prodan et al. (1975) reported that inhalation exposure to high concentrations of vinyl

chloride for two hours has a narcotic effect described by phases of excitement, tranquillity and

then death. The most sensitive experimental animals were mice, with 70% mortality at 107

mg/L, followed by rats, with 23% mortality at 375 mg/L, guinea pigs, with 75% mortality at 600

mg/L, and rabbits, with 50% mortality at 600 mg/L, corresponding to median lethal doses

(LD50s) of 27 419, 47 640, 236 215 and 263 215 ppm for the four species, respectively.

9.2.2 Subchronic exposure

Administration of vinyl chloride monomer dissolved in soybean oil by gavage to groups

of Wistar rats (30 per group) at doses of 0, 30, 100 or 300 mg/kg bw per day, 6 days/week, for 13

weeks did not result in adverse effects at the 30 mg/kg bw per day level. A dose-related increase

in relative liver weight was observed at the two highest dose levels; however, the increase was

statistically significant only at 300 mg/kg bw per day (Feron et al., 1975).

Inhalation exposure of guinea pigs, rats, rabbits and dogs to 50 ppm (130 mg/m3), 100

ppm (260 mg/m3), 200 ppm (540 mg/m

3) or 500 ppm (1300 mg/m

3vinyl chloride for 7


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29

hours/day, 5 days/week, for 26 weeks did not induce any adverse effects at 50 ppm, in terms of

appearance, growth, haematology, liver weight and mortality; however, rats exposed to 100 ppm

had increased liver weights, one of the more sensitive indicators of hepatotoxicity (Torkelson et

al., 1961). Exposure to 200 ppm resulted in increased relative liver weight in male and female

rats, but there was no biochemical or microscopic evidence of liver damage; rabbits exhibited

histological changes (characterized as granular degeneration and necrosis with some

vacuolization and cellular infiltration) in the centrilobular area of the liver. No effects were

observed in guinea pigs or dogs exposed to 200 ppm. Histopathological lesions of the liver

(centrilobular granular degeneration) and increased organ weight occurred in rats exposed to 500

ppm.

9.2.3 Long-term exposure and carcinogenicity

Vinyl chloride administered by inhalation or ingestion induces neoplasms at multiple

sites in several species of animals. In the rat, mouse and hamster, it has induced hepatic

haemangiosarcomas (equivalent to ASL in humans), Zymbal gland tumours, nephroblastomas,

pulmonary and mammary gland tumours and forestomach papillomas.

The minimum dose at which compound-related tumours were induced by inhalation (4

hours/day, 5 days/week) was 10 ppm (26 mg/m3) for 52 weeks for rats, 50 ppm (130 mg/m

3) for

30 weeks for mice and 500 ppm (1300 mg/m3) for 30 weeks for hamsters (Maltoni et al., 1981).

When vinyl chloride in PVC powder was administered orally to rats, the minimum effective dose

of vinyl chloride (causing liver tumours) was 1.7 mg/kg bw per day (Til et al., 1991).

The first experimental data on the carcinogenic effects of vinyl chloride in rats were

published by Viola et al. (1971). Male Wistar rats exposed by inhalation to very high doses (30

000 ppm) for 4 hours daily, 5 days/week, for 12 months, developed skin, lung and

osteochondroma tumours. Moreover, general central nervous system degeneration, specifically

degeneration of granular cells, Purkinje cells and the cerebellum was observed in 3-month-old

rats.

The most comprehensive carcinogenesis bioassays relevant to the assessment of risk

associated with the ingestion of vinyl chloride are those of Maltoni et al. (1981), Feron et al.

(1981) and Til et al. (1983, 1991). Groups of 40 male and 40 female (80 per group) 13-week-old

Sprague-Dawley rats received gastric intubations of 0, 3.33, 16.65 or 50 mg/kg bw per day of

vinyl chloride dissolved in olive oil, 4–5 times per week for 52 weeks, followed by an extended

observation period (Maltoni et al., 1981). At 136 weeks, no hepatic angiosarcomas were

observed in low-dose and control rats. No dose–response relationship was observed in the

induction of other tumours in these animals. Two nephroblastomas (one in each sex), one

Zymbal gland tumour, one thymic angiosarcoma and one intraabdominal angiosarcoma were

observed in the 50 mg/kg bw per day group; two Zymbal gland carcinomas (one in each sex) and

three nephroblastomas (two in males and one in females) were observed in rats administered

16.65 mg/kg bw per day. Seventeen incidences of ASL (eight in males and nine in females) were

found in the 50 mg/kg bw per day group; 10 ASLs (four in males and six in females) occurred in

rats administered the 16.65 mg/kg bw per day dose (Maltoni et al., 1981).

In another experiment by Maltoni et al. (1981), vinyl chloride doses of 0.003, 0.3 or

1.0 mg/kg bw per day were administered by stomach tube to 10-week-old rats (75 of each sex

per group), 5 days/week for 59 weeks. At 136 weeks, no exposure-related liver or kidney

tumours were observed in low-dose or control animals. ASL was found in 1/74 males and 2/75

females administered 1.0 mg/kg bw per day and in 1/73 females administered 0.3 mg/kg bw per


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30

day, however, these increased incidences were not statistically significant. When Sprague-

Dawley rats were exposed to high inhalation concentrations (above 10 000 ppm) for 4 hours

daily, 5 days/week, for 52 weeks, ASL, Zymbal gland carcinoma, forestomach tumours and

neuroblastomas increased significantly. Mammary gland tumours developed at 5 ppm and above

in female rats, whereas nephroblastomas occurred in males at 100–2500 ppm. (Maltoni et al.,

1981).

In a rat lifespan carcinogenicity study (Feron et al., 1981), Wistar rats were exposed to a

mixture of vinyl chloride monomer and PVC powder via the diet. Groups of 60–80 rats of each

sex were fed vinyl chloride at doses of 0, 1.7, 5.0 or 14.1 mg/kg bw per day; as a positive

control, vinyl chloride dissolved in soybean oil (300 mg/kg bw) was also administered by

gavage, 5 days/week. The experiment was terminated once 75% mortality was observed in the

control group (135 weeks for males and 144 weeks for females). Hepatic and lung

angiosarcomas were observed in males (27/55, 27/59, 6/56) and females (2/59, 9/57, 29/54) in

the three highest dose groups (5.0, 14.1, 300 mg/kg bw per day), respectively, but not in the low-

dose group or controls. Males at the 5.0 and 14.1 mg/kg bw per day doses developed 3 times

more angiosarcomas than females. HCC and an increased incidence of foci of cellular alteration

were observed at the lowest level (1.7 mg/kg bw per day). Also, centrilobular degeneration,

necrosis and mitochondrial damage were noted in hepatic parenchyma.

Til et al. (1983) did a follow-up study, under the same conditions, except at lower doses

and with 1% PVC instead of the 10% used by Feron et al. (1981); the results are described in Til

et al. (1991). Oral vinyl chloride doses of 0.017, 0.17 and 1.7 mg/kg bw per day (corresponding

to 0.014, 0.13 and 1.3 mg/kg bw per day when only absorbed vinyl chloride is considered) were

administered to groups of 100 males and 100 females for 149 weeks except for the high-dose

group, which consisted of 50 males and 50 females. An increased incidence of liver nodules was

the only neoplastic response in rats administered 0.17 mg/kg bw per day, but both HCC (three

per sex) and ASL (1/49 males, 2/49 females) were observed at the highest dose (1.7 mg/kg bw

per day), with only the incidence of HCC in males being significantly different from that of the

controls (Til et al., 1983, 1991). No ASL was observed at the 1.7 mg/kg bw per day level in the

original study (Feron et al., 1981). Non-neoplastic results in the liver, such as increased cellular

alteration, polymorphism and cyst formation, were observed in the highest exposure group for

males (1.7 mg/kg bw per day). However, basophilic foci were observed in the lowest exposure

groups (0.017 and 0.17 mg/kg bw per day) for females (Til et al., 1983, 1991); these are not

considered as a precursor of hepatocellular tumour formation, as they arise at a different location

(U.S. EPA, 2000b). The no-observed-adverse-effect level (NOAEL) for tumour induction in rats

was estimated by the authors to be 0.13 mg/kg bw per day (Til et al., 1983, 1991).

The only carcinogenic bioassay in which vinyl chloride was administered to rats in

drinking water is the unpublished work of Evans et al. (ECETOC, 1988). Groups of male and

female (150 per group) Wistar rats received vinyl chloride in drinking water at concentrations of

0, 2.5, 25 or 250 mg/L (equivalent to daily intakes of approximately 0, 0.12, 1.2 or 12 mg/kg bw

per day for males and 0, 0.22, 2.2 or 22 mg/kg bw per day for females) for up to 152 weeks,

except for males and females of the highest dose group, which received the dose for 115 and 101

weeks, respectively. In rats receiving the highest dose, there was a significantly higher incidence

of ASL (8/50 males, 8/49 females) and hepatomas (HCC) (3/50 males, 3/49 females). Only 1 of

the 47 males developed hepatic angiosarcomas in the 25 mg/L dose group. There was no dose–

response relationship in the development of kidney and brain tumours in these animals.


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31

In a reproductive and developmental toxicity study on Sprague-Dawley rats (Thornton et

al., 2002), an increase in liver weight was observed at 10, 100 and 1100 ppm in all F0 rats and at

100 and 1100 ppm in F1 male rats exposed by inhalation under the conditions described in

Section 9.2.5. In maternal rats exposed to 100 ppm, the kidney relative to body weight ratio was

statistically significantly increased, while in the 1100 ppm exposed group, the organ relative to

body weight ratios for both kidney and liver were statistically significantly increased.

Female CD-1 and B6C3F1 mice, Fischer-344 rats and Golden Syrian hamsters were

exposed to fixed concentrations of vinyl chloride (50, 100 and 200 ppm, respectively) for 6 hours

daily, 5 days/week, for 6, 12, 18 and 24 months (Drew et al., 1983). When exposed after

8 months of age, all animals showed a decrease in their length of survival. Every species

developed at least three types of cancer, including ASL, mammary gland adenocarcinomas,

HCC, lung carcinomas and stomach adenomas. Vinyl chloride induced ASL in all three species

(Maltoni et al., 1984).

Different authors have reported different cancer type incidences among mammalian

species. Drew et al. (1983) found a 4- to 5-fold higher incidence of cancer than did Maltoni et al.

(1981). Nevertheless, this could be explained by younger age of exposure and longer exposure

period in the study by Drew et al. (1983). Accordingly, Bi et al. (1985) and Lee et al. (1978)

found an increased occurrence of lung sarcoma in Wistar rats exposed to 100 and 3000 ppm

vinyl chloride in air (6 hours daily, 6 days/week, for 18 months), although at a lower incidence

than ASL; lung sarcoma was not found in mice, however, mammary gland carcinoma,

adenocarcinoma or carcinoma has been reported in mice but not in rats (Lee et al., 1978; Drew et

al., 1983).Animals exposed at a young age developed more cancers (Lee et al., 1978; Drew et al.,

1983; Maltoni et al., 1984; Bi et al., 1985). Swiss mice appear to be more sensitive than B6C3F1

mice, as they reportedly develop lung carcinomas after 6 months of exposure, suggesting an

interspecies variability. Both strains developed ASL and mammary gland carcinomas (Maltoni et

al., 1984). In hamsters, the highest incidence of cancer was reported for those exposed for their

first 12 months of age compared with those exposed after 12 months of age (Drew et al., 1983).

Rats exposed after 12 months of age failed to develop vinyl chloride–related neoplasms, whereas

a shorter latency of 6 months resulted in a significant increase in mammary gland

adenocarcinomas, HCC and ASL. Rats were the only species that developed Zymbal gland

carcinomas, nephroblastomas or neuroblastomas, and HCC; however, the HCC response did not

seem to correlate with the dose. Hamsters did not develop mammary carcinomas, lung adenomas

or hepatomas (Maltoni et al., 1984; Whysner et al., 1996); however, they were the only species

to develop acoustic duct epithelial tumours (Maltoni et al., 1984). Apart from the latter result,

mice and hamsters are not known to develop any additional tumours not reported in rats (Maltoni

et al., 1984). Increasing the exposure for more than a year in rats or 6 months in mice and

hamsters generally did not significantly increase the development of cancer if the exposure

began early in life (Drew et al., 1983).

9.2.4 Mutagenicity/genotoxicity

DNA etheno adducts, naturally occurring in bacteria and animals, can be formed and

detected in mammals (mouse, rat, monkey, human, hamster) in vivo and in bacteria and yeast in

vitro if vinyl chloride is pre-incubated with a mammalian microsomal system (Bartsch et al.,

1975; Laib and Bolt, 1977; Swenberg et al., 1992, 2000; Dogliotti, 2006).


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32

9.2.4.1 In vitro

The Ames test indicated that vinyl chloride and its metabolites are mutagenic (Rannug et

al., 1974; Bartsch et al., 1975). Mutations increase with dose and with increasing time of

exposure (Malaveille et al., 1975; Bartsch et al., 1976, 1979; IARC, 1979; ECETOC, 1988). The

addition of liver human and rat S9 activation system fractions (Rannug et al., 1974; Bartsch et

al., 1975; Bartsch et al., 1975; Malaveille et al., 1975; Sabadie et al., 1980), either pre-incubated

or not with P450 inducers (phenobarbital, 3-methylcholanthrene or Aroclor 1254), and a reduced

nicotinamide adenine dinucleotide phosphate (NADPH) generating system stimulated the

mutagenicity of vinyl chloride in Salmonella typhimurium strains TA1530, TA1535 and G-46

(Malaveille et al., 1975; Loprieno et al., 1976.

Rat hepatic microsomes co-exposed to CEO directly or generated after incubation with

vinyl chloride and polyadenosine or polycytidylic acid (artificial cytidine) reportedly form

ribonucleic acid (RNA) adducts (Laib and Bolt, 1977, 1978; Guengerich and Watanabe, 1979).

CEO and CAA produce adducts that induce transversions (A↔T) but mainly transitions

(GC→AT) in S. typhimurium and in key mammalian genes, such as p53 and k-ras (Matsuda et

al., 1995; Barbin, 2000; Gros et al., 2003). CEO alone was found to be much more potent than

CAA in inducing reverse mutations in S. typhimurium (Malaveille et al., 1975; Loprieno et al.,

1976; Bartsch et al., 1979) and in Escherichia coli strains A3, A11, A23, A58, A88, A446 and

A46 (Barbin et al., 1985; Perrard, 1985) at concentrations as low as 0.1 mM for 1 hour. The

addition of epoxide hydrolase and glutathione S-transferase in vitro, which eliminates CEO, has

been shown to inhibit the binding of CAA and CEO to DNA (Guengerich et al., 1979;

Guengerich and Shimada, 1991).

Mutations in the yeast Saccharomyces pombe increased with time of exposure (5–60

minutes) to vinyl chloride at 16–48 mM concentrations only in the presence of an exogenous

activation system from mouse liver microsomes (Loprieno et al., 1976).

9.2.4.2 In vivo

RNA adducts with adenosine (Laib and Bolt, 1977; Guengerich et al., 1979) and cytidine

(Laib and Bolt, 1978) were found in rats exposed by inhalation to vinyl chloride at 50 ppm for 5

hours. The RNA products were reported to decrease with time after exposure (Bolt et al., 1980).

The more common adduct, albeit not mutagenic, is 7-(2-oxoethyl)-guanosine, with 98%

occurrence (Bolt et al., 1986) in rats exposed to vinyl chloride (Swenberg et al., 1992). It is

followed in lower proportion by the persistent miscoding inducers N2,3-ethenoguanosine and

3,N4-ethenocytosine, both representing ~1% each, and 1,N

6-ethenoadenosine, which rarely

occurs at less than 1% (Fedtke et al., 1990; Basu et al., 1993). When 10-day-old neonatal rats and

their mothers were exposed for 4 days to 600 ppm vinyl chloride, high 7-(2-oxoethyl)-guanosine

and N2,3-ethenoguanosine levels were revealed by GC and high-performance liquid

chromatography, respectively (Fedtke et al., 1990). The N2,3-ethenoguanosine accumulation in

liver of rats was linear between 10 and 1100 ppm (Morinello et al., 2002a) and increased with

exposure time from 2 to 8 weeks when rats were exposed to 500 ppm (Guichard et al., 1996). No

difference was noted between the amount of N2,3-ethenoguanosine in hepatocytes and non-

parenchymal cells in the liver, but weanling rats had 2–3 times the amount of adducts compared

with adults in the same conditions (Morinello et al., 2002a). Moreover, 3,N4-ethenocytosine and

1,N6-ethenoadenosine were found in livers of rats exposed for 2 years to 250 mg/L vinyl chloride

in their drinking water, but no data were given in relation to non-exposed rats (Green and

Hathway, 1978).


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33

In rats, the AT→TA mutation was found at codon 61 of the ha-ras gene after exposure by

inhalation to 500 ppm of vinyl chloride for 8 hours/day for 33 days, leading to liver tumours

(Marion and Boivin-Angele, 1999; Boivin-Angele et al., 2000), and not at codon 13, as found in

humans with ASL. Indeed, ha-ras and ki-ras are involved in rat hepatocyte and human sinusoidal

cell growth activation, respectively. Moreover, none of the codons 12, 13 or 61 that are

associated with human vinyl chloride carcinogenicity were mutated in rat ASL (Marion and

Boivin-Angele, 1999; Barbin, 2000; Boivin-Angele et al., 2000). AT base pair transversion

caused by 1,N6-ethenoadenosine in the p53 gene was associated with rat and human ASL after

exposure to vinyl chloride (Boivin-Angele et al., 2000), revealing consistency between species.

No difference was observed between the amount of 3,N4-ethenocytosine in rats exposed for 4

weeks and allowed to recover for 1 week compared with the ones killed immediately (Morinello

et al., 2002a). Alderley Park rats exposed by inhalation to 1500 ppm vinyl chloride for 6 hours

daily for 5 days had a bone marrow cell chromatid gap frequency similar to that of rats exposed

to the same regime for 3 months (Anderson and Richardson, 1981). However, only two rats per

dose group were used.

Drosophila exposed by inhalation to vinyl chloride at 30–10 000 ppm for 3–17 days had

increased mature sperm recessive lethal mutations, but no chromosomal aberrations were

observed (Verburgt and Vogel, 1977). However, no dominant lethal effects were observed up to

gestational days 12–14 after exposure of male CD-1 mice to vinyl chloride at 10 000 ppm for 4

hours daily for 5 days or at 5000 ppm for 4 hours daily, 5 days/week, for 10 weeks (Himeno et

al., 1983). Female NMR mice and female Chinese hamsters exposed by inhalation to vinyl

chloride at 500 ppm for 5 days and at 12 500 ppm for 6 hours, respectively, had increased single

strand breaks (Basler and Rohrborn, 1980; Walles and Holmberg, 1984).

9.2.5 Reproductive and developmental toxicity

No significant embryotoxic, fetotoxic or teratogenic effects were observed in groups of

pregnant CF-1 mice, Sprague-Dawley rats or New Zealand White rabbits exposed 7 hours/day

via inhalation to vinyl chloride at doses of 50 or 500 ppm on days 6–15 of gestation (mice) or at

doses of 500 or 2500 ppm on days 6–15 (rats) or days 6–18 (rabbits) of gestation (John et al.,

1981). Maternal toxicity, such as higher death rate, decreased feed consumption and increased

liver weight, was observed in mice and rats exposed to 500 ppm and 2500 ppm, respectively.

Fetal effects consisted of delayed skeletal development in mice and an increase in the incidence

of ureter dilation in rats after exposure to a maternally toxic dose (John et al., 1981).

The dose–response changes in the reproductive system of rats exposed to vinyl chloride

were evaluated by Bi et al. (1985). Wistar rats were exposed chronically for 6 hours daily, 6

days/week, for 3, 6, 12 or 18 months to air concentrations of 0, 10, 100 and 1000 ppm. The

authors observed a significant dose–response decrease in testis weight at 100 and 1000 ppm,

accompanied by perturbations in the spermatogenesis process, including fusion of spermatids

and swelling and necrosis of seminiferous tubule cells, with the severity of these effects directly

related to the vinyl chloride concentration. According to Heywood and James (1978),

approximately 20% of rats fed under normal conditions developed testicular atrophy. Sokal et al.

(1980) exposed rats to vinyl chloride at 50, 500 and 20 000 ppm for 10 months. Degeneration of

the seminiferous tubule cells and perturbations in spermatogenesis were reported; however, these

effects did not increase in a dose-responsive fashion at higher concentrations. The fertility of the

males, the capacity to generate offspring and the reversible potency of vinyl chloride were not


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34

examined. Based on these two studies, further research is needed to determine a clear

relationship between vinyl chloride and reproductive effects.

A more recent vinyl chloride inhalation investigation on embryo-fetal development and

reproduction in rats was carried out by Thornton et al. (2002). Four groups of F0 rats were

subchronically exposed to vinyl chloride. Males and females (120 of each sex) were exposed for

a 10-week pre-mating period and a 3-week mating period, followed by continued exposure for

males and 20 days of exposure for gestational females to 0, 10, 100 or 1100 ppm for 6 hours/day.

Thirty pups of each sex were selected from each of the four groups. The F1 generation was also

exposed to the same conditions. F0 and F1 animals were examined twice daily for toxic effects.

Physical evaluation of F1 and F2 pups was done on lactation days 0, 4, 7, 14, 21 or 25.

Macroscopic and microscopic examinations of the reproductive organs were executed at weaning

for 15 male and 15 female F1 and F2 pups. Then, sperm quality was analysed for F0 and F1

animals of each of the four groups. Supporting John et al. (1981), this study revealed no

alteration of embryo-fetal development, teratogenicity or reproduction in the four groups of vinyl

chloride–exposed rats. Body weight, pregnancy rates, postmortem observations, uterine status,

feed consumption and duration of gestation were all unaffected during the pre-mating, mating

and post-mating periods. The reproductive organs did not show any signs of adverse effects,

including sperm motility, number and morphology (Thornton et al., 2002). In the F1 pups, the

live birth index was lower for the 1100 ppm group (0.98), whereas the viability was lower for the

10 and 100 ppm groups (0.89 and 0.88, respectively). Still, the authors stated that historic data

supported these results. For the F2 litter, the authors found a reduced pup number in the 1100

ppm group compared with the F2 controls; however, an increased viability was reported for the

F2 litter exposed to 10, 100 and 1100 ppm. No dose–response relationship for birth rate was seen

after vinyl chloride exposure (Thornton et al., 2002). The authors determined a no-observed-

adverse-effect concentration (NOAEC) of 1100 ppm for embryo-fetal development and

reproduction in rats.

9.2.6 Juvenile sensitivity

Rodent studies have shown that animals less than 4 weeks old appear to be more

susceptible to the formation and persistence of DNA adducts induced by vinyl chloride (Grosse

et al., 2007). Morinello et al. (2002a) found that concentrations of N2,3-ethenoguanine were 2- to

3-fold higher in weanlings than in adults exposed for the same amount of time. The available

data indicate that the cancer risk from a relatively short-term exposure in juveniles is

approximately equal to the risk from long-term exposure in adults; several other genotoxic

carcinogens have shown similar results (Ginsberg, 2003).

Laib et al. (1989) , using radiolabelled vinyl chloride, found an 8-fold increase in the

amount of DNA alkylation in the liver of young rats compared with adult rats; this increase was

attributed to increased levels of DNA synthesis per cell in younger rats.

Maltoni and Cotti (1988) examined the effect of age at the start of exposure on vinyl

chloride toxicity by exposing rat breeders (13 weeks old at the start of the experiment) and

offspring (12 days old at the start of the experiment) to vinyl chloride for 104 weeks. Another

group of rat offspring was exposed for 15 weeks; all rats were observed until their death. The

incidence of hepatocarcinomas was highest in the two groups of offspring; the incidence of ASL

was highest in the offspring exposed for 104 weeks. Neuroblastomas, by contrast, occurred with

the highest frequency in rats exposed for 104 weeks, regardless of starting age. The authors

concluded that the incidence of hepatocarcinomas was influenced by the age at the start of


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35

exposure, ASL was influenced by both age at the start of exposure and duration of exposure and

neuroblastomas were influenced only by the duration of exposure.

Cogliano et al. (1996) reviewed data on early-life exposures to vinyl chloride. They

concluded that the cancer risk from a brief early-life exposure (weeks 1–5 for a rat) is

approximately equal to that from chronic exposure to the same concentration in air beginning at

maturity, but that the specific effects from early-life and full-life exposures may be different.

The U.S. EPA (2000b) reviewed data on early-life and adult cancer potencies based on

studies with repeated exposures of juvenile (from birth to 5 weeks of age) and adult animals

(from 13 to 52 weeks after birth) to genotoxic carcinogens, including vinyl chloride. Based

primarily on the Maltoni and Cotti (1988) study, the median ratios of juvenile to adult cancer

potencies for ASL from vinyl chloride exposure ranged from 9.8 to 29 (geometric mean = 14);

the ratios for hepatoma ranged from 32 to 58 (geometric mean = 47). For other cancers resulting

from vinyl chloride exposure, there was no clear trend towards higher cancer risks in juveniles

compared with adults.

9.3 Mode of action

Primary liver cancer or, more specifically, liver angiosarcoma (ASL; a cancer of the liver

blood vessels) is the most severe endpoint that follows oral (food or water) or inhalation

exposure to vinyl chloride, based on consistencies between epidemiological and experimental

animal studies (Albertini et al., 2003).

The first key event in vinyl chloride–induced toxicity is the formation of the oxidized

metabolites CEO and CAA by hepatocyte CYP2E1 (Bolt, 1986; Barbin and Bartsch, 1989;

Albertini et al., 2003). Metabolites migrate by a cell to cell passage mechanism from hepatocyte

P450 sites to the sinusoidal cells (Morinello et al., 2002b), where ASL originates.

The second key event is the generation of DNA adducts (IPCS, 1999; Holt et al., 2000).

Highly reactive CEO is the major metabolite involved in their formation. The mode of action is

supported by the fact that the toxicokinetics of the metabolite production, dependent on the

activity level of CYP2E1 and the conjugation with glutathione catalyzed by glutathione S-

transferase, are correlated to the adduct formation (IPCS, 1999; U.S. EPA, 2000b). This second

key event is characterized by the persistence of the DNA adducts. Sinusoidal cells express DNA

repair enzymes at lower levels than do hepatocytes (metabolism site), which may explain their

higher amount of DNA etheno adducts (Swenberg et al., 1999; Holt et al., 2000; U.S. EPA,

2000b; Morinello et al., 2002a). After 4 weeks of exposure of rats to vinyl chloride at 1100 ppm,

recovery for 5 days significantly lowered the amount of N2,3-ethenoguanosine in rat hepatocytes,

but not in non-parenchymal cells, compared with the animals sacrificed immediately after

exposure (Morinello et al., 2002a). Differences in the time of repair were observed between the

three common DNA adducts in rats following exposure to vinyl chloride at 600 ppm for 4 hours

daily over 5 days; a longer repair time was observed with 3,N4-ethenocytosine and 1,N

6-

ethenoadenosine (Swenberg et al., 1992; Dosanjh et al., 1994;OEHHA, 2000; Dogliotti, 2006).

The third key event is the formation of mutations specific to vinyl chloride (Bolt, 2005).

The etheno adducts, which are the more persistent, but also the least numerous (~2%), lead to

base pair transition and transversion mutations in cell growth regulator genes (Swenberg et al.,

2000). In fact, rare A→T transversions in the p53 gene have been found in three out of six ASL

cases in vinyl chloride workers (Hollstein et al., 1994), and a linear trend in mutant p53

expression as a function of workers’ exposure intensity was found (Marion and Boivin-Angele,

1999; Wong et al., 2002; Luo et al., 2003). This mutation is chemical specific, as it is not found


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36

in Thorotrast (a radioactive thorium dioxide solution)-induced ASL and is uncommon in

sporadic ASL (Barbin, 2000). Vinyl chloride workers with ASL have prominent ki-ras activating

GC→AT transition mutations at codon 13 (Marion et al., 1991; De Vivo et al., 1994; Marion and

Boivin-Angele, 1999). Vinyl chloride also produces sister chromatid exchanges, clastogenicity

and micronuclei in humans (U.S. EPA, 2000b).

The fourth key event is the effect of genotoxicity on loss of cell cycle regulation and

tumour progression (IARC, 2008). Worker exposure intensities were associated with p53 and

Asp13-p21-ki-ras mutant protein expression levels (De Vivo et al., 1994; Trivers et al., 1995;

Weihrauch et al., 2000, 2001; Luo et al., 2003). The biological plausibility is supported by the

association of the p53 and ras mutations with ASL and HCC development in vinyl chloride

workers (Weihrauch et al., 2000). DNA methylation of p23INK4A

, a gene that inhibits cell cycle

progression, was also observed in a cohort of vinyl chloride workers with HCC (Weihrauch et

al., 2001).

The vinyl chloride non-cancerous mode of action is not as clearly defined as the

cancerous process (U.S. EPA, 2000b).

10.0 Classification and assessment Vinyl chloride has been classified by IARC, the U.S. Department of Health and Human

Services and the U.S. EPA as a known human carcinogen (Group 1 carcinogen), with sufficient

evidence of cancer in both humans and animals. Health Canada classifies vinyl chloride as a

Group 1 carcinogen (carcinogenic to humans). This is consistent with the classifications

established by IARC and the U.S. EPA.

The effects of vinyl chloride exposure have been studied in humans and experimental

animals, with similar outcomes reported in all species. Liver and neurological effects have been

observed consistently in workers as well as several animal species exposed to vinyl chloride over

different exposure durations. Neurological effects have been observed only following inhalation

exposures; however, liver effects have been reported following both medium- and long-term

inhalation and long-term oral exposures. The sensitivity of the liver to vinyl chloride exposure is

supported by the mode of action, as outlined in Section 8.5. The key factors supporting the liver

as the main target organ for cancer and non-cancer effects from vinyl chloride exposure are the

prevalence of mixed-function oxidase activity, specifically CYP2E1, in the liver and the

generation of highly reactive metabolites, which have been shown to bind to DNA as a result of

vinyl chloride metabolism.

Health Canada has considered both cancer and non-cancer endpoints in deriving a

guideline value. The results from both the cancer and non-cancer risk assessment approaches are

described below.

10.1 Cancer risk assessment

The association between occupational exposure to vinyl chloride and the development of

ASL is one of the best characterized cases of chemical-induced carcinogenicity in humans. ASL

is an extremely rare tumour type in the general population; in fact, primary liver cancer of all

types (including ASL) is uncommon in Canada, with an estimated 2,000 new cases for 2012

among an estimated total of 186,400 new cases of all cancers (Canadian Cancer Society’s

Steering Committee on Cancer Statistics, 2012). With the emergence of vinyl chloride

manufacturing, most of the reported ASL cases in North America have been associated with


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37

occupational vinyl chloride exposure. The association of vinyl chloride with ASL in numerous

epidemiological studies has been supported by findings in rats, mice and hamsters exposed to

vinyl chloride through the oral and inhalation routes. Animal data were used for estimating the

cancer potency of vinyl chloride in humans, as exposure data deficiencies in the current vinyl

chloride occupational exposure studies prevent their use for risk assessment. A PBPK model was

used to determine the liver concentration of the active vinyl chloride metabolites, as it allows for

a more pharmacologically relevant estimation of the cancer risk than default models

incorporating body surface area correction or allometric scaling, which are adjusted for by the

model. The most appropriate dose metric generated by the PBPK model was identified to be the

amount of vinyl chloride metabolites produced (per litre of liver tissue per day) that interact

directly with DNA in both animals and humans.

PBPK modeling allows for the calculation of excess cancer risks based on the estimation

of internal dose of vinyl chloride liver metabolites in humans exposed to vinyl chloride through

drinking water. PBPK modeling accounted for metabolic differences between animals and

humans as well as metabolic differences between high and low exposure levels. Both the Feron

et al. (1981) and Til et al. (1991) studies were used for cancer risk assessment, given the

appropriate route of exposure used (oral ingestion), the adequate sample sizes and appropriate

duration of exposure (lifetime). The external doses from these studies were inputted into the rat

PBPK model to determine the daily internal doses of vinyl chloride metabolites generated per

litre of liver tissue for several of the reported cancer endpoints in both male and female rats.

These daily internal doses were then analysed using the multistage cancer model from BMDS

(U.S. EPA, 2010) to determine the most appropriate point of departure to input into the human

PBPK model. The cumulative lifetime internal doses of vinyl chloride liver metabolites

associated with an excess cancer risk of 10−4

, 10−5

and 10−6

for combined liver cancers

(neoplastic nodules, HCC and ASL) in male and female rats were determined as the most

appropriate inputs into the human PBPK model to estimate the external human doses associated

with each risk level for a lifetime (70 years) exposure. The external human doses associated with

an excess risk of combined liver cancers of 10−4

, 10−5

and 10−6

were estimated as 4.19 × 10-4

,

4.19 × 10-5

and 4.19 × 10-6

mg/kg bw per day, respectively; these doses were derived from an

oral human slope factor of 0.24 (mg/kg bw per day)-1

.

The cancer risk estimates for combined liver cancers in females from Feron et al. (1981)

resulted in the most conservative cancer risk estimate; therefore, combined female liver tumours

were chosen as the key endpoint for cancer risk assessment. Although neoplastic nodules may

not necessarily progress to malignancy, including this endpoint avoids any potential

underestimation of the total cancer risk from vinyl chloride exposure. The combined liver tumour

endpoint is also protective of lung angiosarcoma, as the estimated risks for lung angiosarcoma

were lower than those for combined liver tumours , and animals displaying this cancer endpoint

in the Feron et al. (1981) study also had ASL, suggesting metastases from the liver.

Evidence from animal studies suggests that very young children may be more sensitive to

the carcinogenic effects of vinyl chloride due to increased DNA adduct formation and liver

tumour incidence observed in animals under five weeks of age exposed to vinyl chloride

compared to animals exposed after maturity (see Sections 9.1.6 and 9.2.6). In reviewing cancer

potency data from early-life and adult exposures to vinyl chloride, the U.S. EPA (2000b) has

suggested that that the full lifetime cancer risk for vinyl chloride can be approximated by adding

the risks from exposures in early life and adulthood since, for example, the incidence of

angiosarcoma following after short-term, early-life exposure is approximately equal to that


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38

following long-term exposure starting after maturity. As a result, the U.S EPA (2000b)

concluded that continuous lifetime exposure from birth would approximately double cancer risk,

and recommended that if continuous exposure to vinyl chloride were to occur from birth, a

twofold increase should be applied to the adult slope factor in order to protect young children

who may be more sensitive to vinyl chloride exposure.

Although early-life data in humans is lacking, many of the factors likely to be responsible

for early-life sensitivity in animals also pertain to humans. Such factors include rapid cell

division during early life as well as dosimetric considerations such as increased water intake per

unit body weight and more rapid blood flow to liver. As a result, the approach used in this

document is consistent with that of the U.S. EPA, and an additional 2-fold uncertainty factor is

applied to protect young children if exposure to vinyl chloride were to occur from birth.

The concentrations of vinyl chloride in drinking water representing a lifetime excess

combined liver cancer risk of 10−6

and 10−5

in adult humans exposed to 3.8 L-eq of water daily

(see Section 8.4) are 0.08 and 0.8 µg/L, respectively. These concentrations are higher than the

values of 0.013 and 0.13 µg/L calculated using traditional linear extrapolation with allometric

scaling. Given the animal evidence of early-life sensitivity to vinyl chloride, if lifetime exposure

was to occur from birth, then the above concentrations for adults should be divided by two to

protect young children whom may be more sensitive to vinyl chloride. Therefore, the resulting

health-based values (HBVs) for vinyl chloride in drinking water representing a lifetime excess

combined liver cancer risk of 10−6

and 10−5

for early life exposure are 0.04 and 0.4 µg/L,

respectively.

The results that incorporate metabolite generation rates (from PBPK modeling) are

considered to represent a more reasonable estimate of human risk from exposure to vinyl

chloride than simple linear extrapolation with the incorporation of an allometric scaling factor to

account for metabolic differences between rats and humans.

10.2 Non-cancer risk assessment

The most appropriate study for a non-cancer risk assessment is Til et al. (1991), as it

represents a well-controlled study with a large sample size as well as an appropriate duration and

route of exposure (orally through the diet). The most appropriate endpoint is liver cell

polymorphism, as it represents an effect in the liver that is sensitive to both inhalation and oral

exposures to vinyl chloride (ATSDR, 2006). Liver cell polymorphism is not considered a

precursor to carcinogenicity, as it is an effect observed in both the nucleus and cytoplasm of the

liver cells and therefore is considered to be a toxic effect rather than a carcinogenic effect (Schoental

and Magee, 1957, 1959; Afzelius and Schoental, 1967, U.S. EPA, 2000b). Additionally, the

lowest-observed-adverse-effect level (LOAEL) and NOAEL for liver cell polymorphism in both

sexes of rats from the Til et al. (1991) study represent the lowest doses identified in the literature

for any chronic effect resulting from vinyl chloride exposure.

PBPK modeling was used to determine an external human dose corresponding to an

external NOAEL of 0.13 mg/kg bw per day for combined moderate and severe liver cell

polymorphism in female rats from Til et al. (1991); female rats were found to be more sensitive

than males possibly due to a higher internal dose received. Using a rat PBPK model, the internal

dose of vinyl chloride metabolites in the liver resulting from exposure to 0.13 mg/kg bw per day

was determined as 2.85 mg/L of liver tissue per day. This internal dose was then inputted into the

human PBPK model in order to determine a human external dose required (when consuming

1.5 L of drinking water per day for 70 years) to generate the same concentration of liver


______________________________________________________________________


39

metabolites; the resulting human external dose corresponding to an internal daily dose 2.85 mg/L

of liver metabolites was determined as 0.224 mg/kg bw per day.

Using the human external dose derived above as the most appropriate point of departure,

the tolerable daily intake (TDI) for vinyl chloride can be calculated as follows:

TDI = 0.224 mg/kg bw per day

25

= 0.009 mg/kg bw per day

where:

0.224 mg/kg bw per day is the human external dose for combined moderate and severe

liver cell polymorphism derived through PBPK modeling as described above; and

25 is the uncertainty factor (×2.5 for interspecies toxicodynamic variability [see below]

and ×10 for intraspecies variability).

The interspecies uncertainty factor can be divided in two components: a toxicokinetic

(delivered dose) component (4.0) and a toxicodynamic (differential tissue sensitivity) component

(2.5) (IPCS, 2005). PBPK modeling accounts for differences in the toxicokinetics between

animals and humans; as a result, the toxicokinetic component of the interspecies uncertainty

factor (4.0) can be removed from the TDI calculation. As the toxicodynamic variation (relating

to tissue sensitivity) between animals and humans for vinyl chloride is not well known, the

toxicodynamic portion of the interspecies uncertainty factor was retained for determining the

TDI. Retention of the toxicodynamic portion of variation between animals and humans is further

supported by the uncertainty surrounding the basic mode of action for non-cancer liver effects as

well as the limited evidence of human susceptibility to non-cancer liver effects from

occupational exposure to vinyl chloride.

Using the above TDI, a health-based value (HBV) for vinyl chloride in drinking water

can be derived as follows:

HBV = 0.009 mg/kg bw per day × 70 kg × 0.20

3.8 L-eq/day

= 0.033 mg/L

≈ 0.03 mg/L (30 µg/L)

where:

0.009 mg/kg bw per day is the TDI as derived above;

70 kg is the average body weight of an adult;

0.20 is the proportion of the daily intake allocated to drinking water; this is a default

value, as there are insufficient data to calculate the actual value; and

3.8 L-eq/day is the daily volume of water consumed by an adult, accounting for multiple

routes of exposure from showering and bathing, as determined in Section 8.4.


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40

10.3 Comparison of cancer and non-cancer risk assessments

In Section 10.1, the concentrations of vinyl chloride in drinking water associated with a

lifetime excess risk of combined liver tumours of 10−6

and 10-5

were determined as 0.08 and

0.8 µg/L, respectively, for exposure during adulthood; if exposure was to occur from birth, these

concentrations are to be reduced to 0.04 and 0.4 µg/L, respectively. Using a TDI approach in

Section 10.2, a health-based value that is protective of liver cell polymorphism (moderate and

severe) was determined to be 30 µg/L. As the cancer risk assessment resulted in a more

conservative value for vinyl chloride in drinking water compared with that generated by the non-

cancer approach, the cancer risk assessment approach was determined as the most appropriate

approach for developing the maximum acceptable concentration (MAC) in drinking water.

10.4 International considerations

The U.S. EPA maximum contaminant level (MCL) for vinyl chloride in drinking water

is 0.002 mg/L (2 µg/L) based on liver cancer. The U.S. EPA (2000b) extrapolated its cancer

slope factors as well as a non-cancer inhalation reference concentration (RfC) and oral human

reference dose (RfD) from the Clewell et al. (1995) PBPK model. For the cancer risk assessment,

the U.S. EPA used the data from the Feron et al. (1981) study to derive an a human oral cancer

slope factor of 0.72 per mg/kg bw/day for total liver cancers (liver angiosarcoma, hepatocellular

carcinoma and neoplastic nodules) resulting from continuous lifetime exposure during

adulthood. A twofold increase to 1.4 per mg/kg bw/day is recommended to account for

continuous lifetime exposure starting at birth. For the non-cancer assessment, the integration of

the rat NOAEL of 0.13 mg/kg bw per day for induction of non-cancer cell polymorphism (Til et

al., 1983, 1991) generated a rat target tissue concentration of 3 mg of metabolites/L of liver (U.S.

EPA, 2000b). Assuming a consumption of 2 L water per day, 70 kg person, the PBPK-derived

human dose given orally that would generate the same target tissue concentration (TTC) equal to

0.09 mg/kg bw per day, resulting in an RfD of 0.003 mg/kg bw per day.

The WHO (2004) drinking water quality guideline of 0.3 µg/L is based on the U.S. EPA

(2000b) oral slope factor and a 10-5

cancer risk. A concentration of vinyl chloride in drinking

water of 0.5 μg/L was calculated as being associated with an upper-bound excess risk of liver

tumours of 10-5

for lifetime exposure beginning at adulthood. However, with uncertainty

regarding differences in sensitivity during early life exposure and the assumption by the U.S.

EPA (2000b) that continuous lifetime exposure from birth would double cancer risk, the WHO

divided the level for adults by a 2-fold uncertainty factor and rounded up to 0.3 µg/L to arrive at

its drinking water guideline value.

The California EPA (OEHHA, 2000) established a non-regulatory public health goal

(PHG) of 0.05 µg/L for vinyl chloride in drinking water. The PHG is based on an inhalation

cancer slope factor of 0.27 (mg/kg bw per day)-1

for lung cancer observed in mice from an

inhalation study by Drew et al. (1983). A value of 3 µg/L was calculated based on non-cancer

effects of vinyl chloride based on liver cell polymorphism and hepatic cysts in male and female

rats. The non-cancer PHG incorporates a 100-fold uncertainty factor and a water exposure rate of

7.1 L/day that includes 5.1 L-equivalents to account for exposure by inhalation and dermal

exposure from bathing or showering. California’s current drinking water standard (MCL) for vinyl

chloride is 0.5 µg/L, which was adopted in 1989.

The Australian Drinking Water Guideline for vinyl chloride of less than 0.0003 mg/L

(0.3 µg/L) is based on considerations of health effects (cancer) and the limit of determination

(NHMRC, 2004).


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41

11.0 Rationale Vinyl chloride has been classified as a human carcinogen (Group 1 carcinogen) with

sufficient evidence of cancer in both humans and animals. Entry into drinking water may result

from industrial discharges to source water from chemical and latex manufacturing or from

leaching of the entrapped monomer from polyvinyl chloride pipe. Vinyl chloride may also be

formed in groundwater and the environment through the biodegradation of synthetic solvents

such as trichlorethylene, trichloroethane and tetrachloroethylene.

The effects of vinyl chloride exposure have been studied in humans and animals, with

similar outcomes reported in all species. Liver and neurological effects have been observed

consistently in workers as well as several animal species exposed to vinyl chloride over different

exposure durations. Liver cancer is the most serious endpoint that follows oral (food or water) or

inhalation exposure to vinyl chloride, based on consistencies between epidemiological and

experimental animal studies. Although many other tumour types have been reported in animals

following vinyl chloride exposure, there is little consistency in the observed tumour types across

species.

Given the volatility of vinyl chloride, a multi-route exposure assessment was performed

using PBPK modeling in order to determine any additional exposure by dermal or inhalation

exposure during showering or bathing. Additional litre-equivalent (L-eq) exposures of 1.9 L-eq

from dermal exposure and 0.4 L-eq from inhalation exposure during showering or bathing were

determined from the human PBPK model and were added to the Canadian drinking water

ingestion rate of 1.5 L/day, resulting in a total estimated L-eq daily exposure of 3.8 L-eq. This

daily exposure was used in both the cancer and non-cancer risk assessments.

PBPK modeling was used to calculate excess cancer risks based on the internal dose of

vinyl chloride metabolites in humans exposed to vinyl chloride through drinking water. Evidence

from animal studies suggests that very young children (less than 5 weeks of age) may be more

sensitive to the carcinogenic effects of vinyl chloride than adults; in fact, current scientific

evidence suggests a 2-fold increased sensitivity if children under the age of 5 weeks are exposed

to vinyl chloride. Therefore, the concentrations representing “essentially negligible” lifetime risk

of combined liver tumours in children less than 5 weeks of age would range from 0.04 to

0.4 µg/L. Health Canada has defined this term as a range from one new cancer above

background levels per 100 000 people to one new cancer above background levels per 1 million

people (i.e., 10-5

to 10-6

). This level is protective of both potential cancer and non-cancer effects

resulting from exposure to vinyl chloride in drinking water.

Air stripping and packed tower aeration are municipal-scale treatment processes, which

can remove vinyl chloride from drinking water to level below 1 µg/L. Alternative processes,

such as ozonation and advance oxidation processes, have been reported to be effective for the

reduction of vinyl chloride from drinking water to below 0.5 µg/L.

There are no certified residential treatment devices currently available for the reduction

of vinyl chloride from drinking water. However, a study conducted on treatment devices using

activated carbon filters demonstrated that they may be effective for the reduction of vinyl

chloride to levels below 2 µg/L. Health Canada recommends that PVC pipes used in the

distribution of drinking water be certified to NSF/ANSI Standard 61, which limits the leaching

of vinyl chloride based on a harmonized regulatory limit of 2 µg/L.

A MAC of 0.002 mg/L (2 µg/L) for vinyl chloride is established based on the following

considerations:


______________________________________________________________________


42

The MAC must be measurable. The U.S. EPA has established a PQL of 0.002 mg/L,

based on the ability of laboratories to measure vinyl chloride within reasonable limits of

precision and accuracy using approved methods. There is no similar process in place to

establish a PQL specific to Canada.

The MAC must be achievable at reasonable cost. Municipal scale treatment technologies

can consistently remove vinyl chloride from drinking water to 0.5 µg/L, which is below

the MAC of 2 µg/L. At the residential level, although there are no treatment units

currently certified to remove vinyl chloride, it is expected that the use of two or more

treatment devices using technologies such as activated carbon would remove vinyl

chloride below the MAC.

NSF/ANSI Standard 61 limits leaching of vinyl chloride into drinking water by ensuring

materials meet a SPAC of 0.0002 mg/L (0.2 µg/L) or less (NSF/ANSI, 2012). The SPAC

is established at one tenth the regulatory value for drinking water, as harmonized between

the U.S. and Canada.

In considering both treatment achievability and the health risks associated with vinyl

chloride exposure from drinking water, the Federal-Provincial-Territorial Committee on

Drinking Water has established a MAC of 0.002 mg/L (2 µg/L). The estimated lifetime risk

associated with ingestion of water containing vinyl chloride at the MAC is 5.0 × 10-5

which is

above the range that is considered to represent “essentially negligible” risk. This value is based

on analytical achievability; as it exceeds the health-based value for the protection of young

children, every effort should be made to maintain vinyl chloride levels in drinking water as low

as reasonably achievable (or ALARA).

As part of its ongoing guideline review process, Health Canada will continue to monitor

new research in this area and recommend any change to the guideline that is deemed necessary.

12.0 References

Adams, J.Q. and Clark, R.M. (1991). Evaluating the costs of packed-tower aeration and GAC for controlling

selected organics. J. Am. Water Works Assoc., 83(1): 49–57.

Afzelius, B.A. and Schoental, R. (1967). The ultrastructure of the enlarged hepatocytes induced in rats with a single

oral dose of retrorsine, a pyrrolizidine (Senecio) alkaloid. J. Ultrastruct. Res., 20: 328–345.

Alberta Department of Environment (2009). Personal communication with K. Pongar.

Albertini, R., Clewell, H., Himmelstein, M.W., Morinello, E., Olin, S., Preston, J., Scarano, L., Smith, M.T.,

Swenberg, J., Tice, R. and Travis, C. (2003). The use of non-tumor data in cancer risk assessment: reflections on

butadiene, vinyl chloride, and benzene. Regul. Toxicol. Pharmacol., 37: 105–132.

Al-Malack, M. (2004). Effect of UV-radiation on the migration of vinyl chloride monomer from unplasticized PVC

pipes. J. Environ. Sci. Health, 39(1): 145–157.

Al-Malack, M. and Sheikheldin, S. (2001). Effect of solar radiation on the migration of vinyl chloride monomer

from unplasticized PVC pipes. Water Res., 35(14): 3283–3290.

Al-Malack, M., Sheikheldin, S., Fayad, N. and Khaja, N. (2000). Effect of water quality parameters on the migration

of vinyl chloride monomer from unplasticized PVC pipes. Water Air Soil Pollut., 120: 195–208.


______________________________________________________________________


43

Anderson, D. and Richardson, C.R. (1981). Issues relevant to the assessment of chemically induced chromosome

damage in vivo and their relationship to chemical mutagenesis. Mutat. Res., 90: 261–272.

Ando, M. and Sayato, Y. (1984). Studies on vinyl chloride migrating into drinking water from polyvinyl chloride

pipe and reaction between vinyl chloride and chlorine. Water Res., 18: 315–318.

Antweiler, H. (1976). Studies on the metabolism of vinyl chloride. Environ. Health Perspect., 17: 217–219.

APHA, American Water Works Association and Water Environment Federation (2005). Standard methods for the

examination of water and wastewater. 21st edition. American Public Health Association, Washington, DC.

ATSDR (2006). Toxicological profile for vinyl chloride. Agency for Toxic Substances and Disease Registry, Public

Health Service, U.S. Department of Health and Human Services, Atlanta, Georgia.

AWWA (1991). Existing VOC treatment installations; design, operation and cost. Report of the Organics

Contaminant Control Committee. Water Quality Division, American Water Works Association, Denver, Colorado

(Report No. 0033986).

Banzer, J.D. (1979). The migration of vinyl chloride monomer from PVC pipe into water. J. Vinyl Technol., 1: 164–

167.

Barbin, A. (1999). Role of etheno DNA adducts in carcinogenesis induced by vinyl chloride in rats. IARC Sci.

Publ., 150: 303–313.

Barbin, A. (2000). Etheno-adduct-forming chemicals: from mutagenicity testing to tumor mutation spectra. Mutat.

Res., 462: 55–69.

Barbin, A. and Bartsch, H. (1989). Nucleophilic selectivity as a determinant of carcinogenic potency (TD50) in

rodents: a comparison of mono- and bi-functional alkylating agents and vinyl chloride metabolites. Mutat. Res., 215:

95–106.

Barbin, A., Besson, F., Perrard, M.H., Bereziat, J.C., Kaldor, J., Michel, G. and Bartsch, H. (1985). Induction of

specific base-pair substitutions in E. coli trpA mutants by chloroethylene oxide, a carcinogenic vinyl chloride

metabolite. Mutat. Res., 152: 147–156.

Bartsch, H., Malaveille, C. and Montesano, R. (1975). Human, rat and mouse liver-mediated mutagenicity of vinyl

chloride in S. typhimurium strains. Int. J. Cancer, 15: 429–437.

Bartsch, H., Malaveille, C., Barbin, A., Bresil, H., Tomatis, L. and Montesano, R. (1976). Mutagenicity and

metabolism of vinyl chloride and related compounds. Environ. Health Perspect., 17: 193–198.

Bartsch, H., Malaveille, C., Barbin, A. and Planche, G. (1979). Mutagenic and alkylating metabolites of halo-

ethylenes, chlorobutadienes and dichlorobutenes produced by rodent or human liver tissues. Evidence for oxirane

formation by P450-linked microsomal mono-oxygenases. Arch. Toxicol., 41: 249–277.

Basler, A. and Rohrborn, G. (1980). Vinyl chloride: an example for evaluating mutagenic effects in mammals in

vivo after exposure to inhalation. Arch. Toxicol., 45: 1–7.

Basu, A.K., Wood, M.L., Niedernhofer, L.J., Ramos, L.A. and Essigmann, J.M. (1993). Mutagenic and genotoxic

effects of three vinyl chloride–induced DNA lesions: 1,N6-ethenoadenine, 3,N

4-ethenocytosine, and 4-amino-5-

(imidazol-2-yl)imidazole. Biochemistry, 32: 12 793–12 801.

Beardsley, M. and Adams, C.D. (2003). Modeling and control of vinyl chloride in drinking water distribution

systems. J. Environ. Eng., 129: 844–851.


______________________________________________________________________


44

Becker, R., Nikolova, T., Wolff, I., Lovell, D., Hüttner, E. and Foth, H. (2001). Frequency of HPRT mutants in

humans exposed to vinyl chloride via an environmental accident. Mutat. Res., 494: 87–96.

Benfenati, E., Natangelo, M., Davoli, E. and Fanelli, R. (1991). Migration of vinyl chloride into PVC-bottled

drinking-water assessed by gas chromatography–mass spectrometry. Food Chem. Toxicol., 29: 131–134.

Berk, P.D., Martin, J.F., Young, R.S., Creech, J., Selikoff, I.J., Falk, H., Watanabe, P., Popper, H. and Thomas, L.

(1976). Vinyl chloride–associated liver disease. Ann. Intern. Med., 84: 717–731.

Bi, W.F., Wang, Y.S., Huang, M.Y. and Meng, D.S. (1985). Effect of vinyl chloride on testis in rats. Ecotoxicol.

Environ. Saf., 10: 281–289.

Boffetta, P., Matisane, L., Mundt, K.A. and Dell, D.S. (2003). Meta-analysis of studies of occupational exposure to

vinyl chloride in relation to cancer mortality. Scand. J. Work Environ. Health;29(3):220–229.

Boivin-Angele, S., Lefrançois, L., Froment, O., Spiethoff, A., Bogdanffy, M.S., Wegener, K., Wesch, H., Barbin,

A., Bancel, B., Trépo, C., Bartsch, H., Swenberg, J. and Marion, M.J. (2000). Ras gene mutations in vinyl chloride–

induced liver tumours are carcinogen-specific but vary with cell type and species. Int. J. Cancer, 85: 223–227.

Bolt, H.M. (1986). Metabolic activation of vinyl chloride, formation of nucleic acid adducts and relevance to

carcinogenesis. IARC Sci. Publ., 70: 261–268.

Bolt, H.M. (2005). Vinyl chloride—a classical industrial toxicant of new interest. Crit. Rev. Toxicol., 35: 307–323.

Bolt, H.M., Kapus, H., Buchter, A. and Bolt, W. (1976). Disposition of (1,2-14

C) vinyl chloride in the rat. Arch.

Toxicol., 35(3): 153–162.

Bolt, H.M., Filser, J.G., Laib, R.J. and Ottenwalder, H. (1980). Binding kinetics of vinyl chloride and vinyl bromide

at very low doses. Arch. Toxicol., Suppl. 3: 129–142.

Bolt, H.M., Laib, R.J., Peter, H. and Ottenwalder, H. (1986). DNA adducts of halogenated hydrocarbons. J. Cancer

Res. Clin. Oncol., 112: 92–96.

Bosetti, C., La Vecchia, C., Lipworth, L. and McLaughlin, J.K. (2003). Occupational exposure to vinyl chloride and

cancer risk: a review of the epidemiologic literature. Eur. J. Cancer Prev., 12: 427–430.

Bowman, R. (2003). Ozone-peroxide advanced oxidation water treatment system for treatment of chlorinated

solvents and 1,4-dioxane. Paper presented at the 9th Symposium in the Groundwater Resources Association of

California’s Series on Groundwater Contaminants, December 10, 2003, San Jose, California.

Bradley, P.M. (2000). Microbial degradation of chlorethenes in groundwater system. Hydrol. J., 8: 104–111.

Bradley, P.M. and Chapelle, F.H. (1996). Anaerobic mineralization of vinyl chloride in Fe(III)-reducing aquifer

sediments. Environ. Sci. Technol., 30: 2084-2086.

Bradley, P.M. and Chapelle, F.H. (2011). Microbial mineralization of dichloroethene and vinyl chloride under

hypoxic conditions. Ground Water Monit. Remediat., 31(4): 39-49.

Buchter, A., Bolt, H.M., Filser, J.G., Goergens, H.W., Laib, R.J. and Bolt, W. (1978). Pharmakokinetik und

Karzinogenese von Vinylchlorid. Arbeitsmedizinische Risikobeurteilung. Verh. Dtsch. Ges. Arbeitsmed., 18: 111–

124.

Buchter, A., Filser, J.G., Peter, H. and Bolt, H.M. (1980). Pharmacokinetics of vinyl chloride in the Rhesus monkey.

Toxicol. Lett., 6: 33–36.


______________________________________________________________________


45

Carroll, W.F. and Eckstein, D. (2001). Vinyl chloride in rural water from pre-1977 applications of PVC pipe. J.

Vinyl Addit. Technol., 7(1): 43–50.

Canadian Cancer Society’s Steering Committee on Cancer Statistics (2012). Canadian Cancer Statistics 2012.

Toronto, Ontario: Canadian Cancer Society; 2012. May. ISSN 0835-2976. Available at: www.cancer.ca/Canada-

wide/Publications.aspx?sc_lang=en

Chiang, S.-Y., Swenberg, J.A., Weisman, W.H. and Skopek, T.R. (1997). Mutagenicity of vinyl chloride and its

reactive metabolites, chloroethylene oxide and chloroacetaldehyde, in a metabolically competent human B-

lymphoblastoid line. Carcinogenesis, 18: 31–36.

Chiu, W.A. and White, P. (2006). Steady-state solutions to PBPK models and their applications to risk assessment I:

Route-to-route extrapolation of volatile chemicals. Risk Anal. 26 (3): 769-780.

Chung, Y., Shin, D., Park, S., Lim, Y., Choi, Y., Cho, S., Yang, J., Hwang, M., Park, Y. and Lee, H. (1997). Risk

assessment and management of drinking water pollutants in Korea. Water Sci. Technol., 36(12): 309–323.

CIS (1999). CPI product profiles: Vinyl chloride/polyvinyl chloride. Camford Information Services, Toronto.

Clark, R.M., Fronk, C.A. and Lykins, B.W., Jr. (1988). Removing organic contaminants from groundwater. Environ.

Sci. Technol., 22(10): 1126–1130 [cited in Dyksen et al., 1992].

Clewell, H.J., Gentry, P.R., Gearhart, J.M., Allen, B.C. and Andersen, M.E. (1995). Considering pharmacokinetic

and mechanistic information in cancer risk assessments for environmental contaminants: examples with vinyl

chloride and trichloroethylene. Chemosphere, 31: 2561–2578.

Clewell, H.J., Gentry, P.R., Gearhart, J.M., Allen, B.C. and Andersen, M.E. (2001). Comparison of cancer risk

estimates for vinyl chloride using animal and human data with a PBPK model. Sci. Total Environ., 274: 37–66.

Clewell, H.J., Gentry, P.R., Covington, T.R., Sarangapani, R. and Teeguarden, J.G. (2004). Evaluation of the

potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry. Toxicol. Sci., 79:

381–393.

Cogliano, V.J., Hiatt, G.F.S. and Den, A. (1996). A quantitative cancer assessment for vinyl chloride: indications of

early-life sensitivity. Toxicology 111:21-28.

Cook, W.A., Giever, P.M., Dinman, B.D. and Magnuson, H.J. (1971). Occupational acroosteolysis. II. An industrial

hygiene study. Arch. Environ. Health, 22: 74–82.

Creech, J.L., Jr. and Johnson, M.N. (1974). Angiosarcoma of liver in the manufacture of polyvinyl chloride. J.

Occup. Med., 16: 150–151.

Crittenden, J.C., Cortright, R.D., Rick, B., Tang, S. and Perram, D. (1988). Using GAC to remove VOCs from air-

stripper off-gas. J. Am. Water Works Assoc., 80(5): 73–84.

Crittenden, J.C., Trussell, R.R., Hand, D.W., Howe, K.J. and Tchobanoglous, G. (2005). Water treatment: principles

and design. 2nd edition. John Wiley & Sons.

Crump, K. (1984). A new method for determining allowable daily intakes. Fund. Appl. Toxicol. 4: 854-871.)

CSA (2009). CSA B137 Series-09 Thermoplastic pressure piping compendium. Canadian Standards Association,

Mississauga, Ontario.


______________________________________________________________________


46

Cummins, M.D. and Westrick, J.J. (1990). Treatment technologies and costs for removing volatile organic

compounds from water: aeration. In: Significance and treatment of volatile organic compounds in water supplies.

N.M. Ram, R.F. Christman and K.P. Cantor (eds.). Lewis Publishers, Chelsea, Michigan.

Davis, J.W. and Carpenter, C.L. (1990). Aerobic biodegradation of vinyl chloride in groundwater samples. Appl.

Environ. Microbiol., 56: 3878–3880.

Dawson, H.E. and McAlary, T. (2009). A compilation of statistics for VOCs from post 1990 indoor air

concentration studies in North American residences unaffected by subsurface vapour intrusion. Ground Water

Monit. Remediat., 29: 60–69.

De Vivo, I., Marion, M.J., Smith, S.J., Carney, W.P. and Brandt-Rauf, P.W. (1994). Mutant c-Ki-ras p21 protein in

chemical carcinogenesis in humans exposed to vinyl chloride. Cancer Causes Control, 5: 273–278.

Dogliotti, E. (2006). Molecular mechanisms of carcinogenesis by vinyl chloride. Ann. Ist. Super. Sanita, 42: 163–

169.

Dosanjh, M.K., Chenna, A., Kim, E., Fraenkel-Conrat, H., Samson, L. and Singer, B. (1994). All four known cyclic

adducts formed in DNA by the vinyl chloride metabolite chloroacetaldehyde are released by a human DNA

glycosylase. Proc. Natl. Acad. Sci. U. S. A., 91: 1024–1028.

Doss, M., Lange, C.E. and Veltman, G. (1984). Vinyl chloride–induced hepatic coproporphyrinuria with transition

to chronic hepatic porphyria. Klin. Wochenschr., 62: 175–178.

Dowideit, P. and von Sontag, C. (1998). Reaction of ozone with ethene and its methyl- and chlorine-substituted

derivatives in aqueous solution. Environ. Sci. Technol., 32: 1112–1119.

Dressman, R.C. and McFarren, E.F. (1978). Determination of vinyl chloride migration from polyvinyl chloride pipe

into water. J. Am. Water Works Assoc., 70: 29–30.

Drew, R.T., Boorman, G.A., Haseman, J.K., McConnell, E.E., Busey, W.M. and Moore, J.A. (1983). The effect of

age and exposure duration on cancer induction by a known carcinogen in rats, mice, and hamsters. Toxicol. Appl.

Pharmacol., 68: 120–130.

Dyksen, J.E. (2005). Aeration and air stripping. In: Water treatment plant design. 4th edition. E.E. Baruth (ed.).

McGraw-Hill.

Dyksen, J.E., Ford, R., Raman, K., Schaefer, J.K., Fung, L., Schwartz, B. and Barnes, M. (1992). In-line ozone and

hydrogen peroxide treatment for removal of organic chemicals. American Water Works Association Research

Foundation, Denver, Colorado.

ECETOC (1988). The mutagenicity and carcinogenicity of vinyl chloride: a historical review and assessment.

European Centre for Ecotoxicology and Toxicology of Chemicals, Brussels. pp. 1–154.

el Ghissassi, F., Barbin, A. and Bartsch, H. (1998). Metabolic activation of vinyl chloride by rat liver microsomes:

low-dose kinetics and involvement of cytochrome P450 2E1. Biochem. Pharmacol., 55: 1445–1452.

Elliott, P. and Kleinschmidt, I. (1997). Angiosarcoma of the liver in Great Britain in proximity to vinyl chloride

sites. Occup. Environ. Med., 54: 14–18.

Environment Canada (1985). Environmental technical information for problem spills: Vinyl chloride. Environmental

Protection Service, Ottawa, Ontario.

Environment Canada (1986). Environmental status report 1979–1984, vinyl chloride industry. Ottawa, Ontario.


______________________________________________________________________


47

Environment Canada (1998). Atlantic Region Federal–Provincial Toxic Chemical Survey of Municipal Drinking

Water Sources 1985–1988.

Environment Canada (2002). River Road. Annual. Ambient Air Quality Measurements: Montreal. Quebec.

Environment Canada (2004). 2002 annual air report data for vinyl chloride. Data provided to Cantox Environmental

by T. Dann, March 2004.

Environment Canada (2006). National Air Pollution Surveillance (NAPS) Network. Annual data summary for vinyl

chloride 2003–2006. Ottawa, Ontario.

Environment Canada (2008). Personal communications from A. Wong, Head, Air Issues and Regulatory Affairs, Air

and Climate Change Section, Environmental Protection Operations Directorate. Ottawa, Ontario.

ESE (1984). Technologies and cost for the removal of volatile organic chemicals from potable water supply (draft).

Environmental Science and Engineering Inc. (ESE No. 84-912-0300).

Fedtke, N., Boucheron, J.A., Walker, V.E. and Swenberg, J.A. (1990). Vinyl chloride–induced DNA adducts. II:

Formation and persistence of 7-(2′-oxoethyl)guanine and N2,3-ethenoguanine in rat tissue DNA. Carcinogenesis, 11:

1287–1292.

Feron, V.J., Speek, A.J., Willems, M.E., van Battum, D. and de Groot, A.P. (1975). Observations on the oral

administration and toxicity of vinyl chloride in rats. Food Cosmet. Toxicol., 13: 633–638.

Feron, V.J., Hendriksen, C.F., Speek, A.J., Til, H.P. and Spit, B.J. (1981). Lifespan oral toxicity study of vinyl

chloride in rats. Food Cosmet. Toxicol., 19: 317–333.

Flournoy, R.L., Monroe, D., Chestnut, N. and Kumar, V. (1999). Health effects from vinyl chloride monomer

leaching from pre-1997 PVC pipe. In: Proceedings of the 1999 AWWA National Conference, Chicago, Illinois.

American Water Works Association, Denver, Colorado. pp. 1–20 (Paper Tu22-4).

Fox, A.J. and Collier, P.F. (1977). Mortality experience of workers exposed to vinyl chloride monomer in the

manufacture of polyvinyl chloride in Great Britain. Br. J. Ind. Med., 34: 1–10.

Fronk, C.A. (1987). Destruction of volatile organic contaminants in drinking water by ozone treatment. Ozone Sci.

Eng., 9: 265-288.

Fucic, A., Barkovic, D., Garaj-Vrhovac, V., Kubelka, D., Ivanic, B., Dabo, T. and Mijic, A. (1996). A nine-year

follow up study of a population occupationally exposed to vinyl chloride monomer. Mutat. Res., 361: 49–53.

Gedigk, P., Muller, R. and Bechtelsheimer, H. (1975). Morphology of liver damage among polyvinyl chloride

production workers. A report of 51 cases. Ann. N. Y. Acad. Sci., 246: 278–285.

Gentry, P.R., Covington, T.R. and Clewell, H.J. III. (2003). Evaluation of the potential impact of pharmacokinetic

differences on tissue dosimetry in offspring during pregnancy and lactation. Regul Toxicol Pharmacol 38:1-16.

Ginsberg, G.L. (2003). Assessing cancer risks from short-term exposures in children. Risk Anal 23(1):19

34.

Government of Canada (2011). Food and Drug Regulations, C.R.C., c. 870, B.23.007. Available at : http://laws-

lois.justice.gc.ca/PDF/C.R.C.,_c._870.pdf

Green, T. and Hathway, D.E. (1975). The biological fate in rats of vinyl chloride in relation to its oncogenicity.

Chem. Biol. Interact., 11: 545–562.


______________________________________________________________________


48

Green, T. and Hathway, D.E. (1977). The chemistry and biogenesis of the S-containing metabolites of vinyl chloride

in rats. Chem. Biol. Interact., 17: 137–150.

Green, T. and Hathway, D.E. (1978). Interactions of vinyl chloride with rat-liver DNA in vivo. Chem. Biol. Interact.,

22: 211–224.

Gros, L., Ishchenko, A.A., and Saparbaev, M. (2003). Enzymology of repair of etheno-adducts. Mutation Research

531: 219–229.

Grosse, Y., Baan, R., Straifr, K., Secretan, B., El Ghissassi, F., Bouvard, V., Altieri, A. and Cogliano, V. (2007).

Carcinogenicity of 1,3-butadiene, ethylene oxide, vinyl chloride, vinyl fluoride, and vinyl bromide. Lancet

Oncology 2007;8:679-80.

Guengerich, F.P. and Shimada, T. (1991). Oxidation of toxic and carcinogenic chemicals by human cytochrome P-

450 enzymes. Chem. Res. Toxicol., 4: 391–407.

Guengerich, F.P. and Watanabe, P.G. (1979). Metabolism of [14

C]- and [36

C]-labeled vinyl chloride in vivo and in

vitro. Biochem. Pharmacol., 28: 589–596.

Guengerich, F.P., Crawford, W.M., Jr. and Watanabe, P.G. (1979). Activation of vinyl chloride to covalently bound

metabolites: roles of 2-chloroethylene oxide and 2-chloroacetaldehyde. Biochemistry, 18: 5177–5182.

Guengerich, F.P., Kim, D.H. and Iwasaki, M. (1991). Role of human cytochrome P-450 IIE1 in the oxidation of

many low molecular weight cancer suspects. Chem. Res. Toxicol., 4: 168–179.

Guichard, Y., el Ghissassi, F., Nair, J., Bartsch, H. and Barbin, A. (1996). Formation and accumulation of DNA

ethenobases in adult Sprague-Dawley rats exposed to vinyl chloride. Carcinogenesis, 17: 1553–1559.

Haarhoff, J. and Cleasby J.L. (1990). Evaluation of air stripping for the removal of organic drinking water

contaminants. Water SA, 16(1): 13–22.

Hand, D.W., Crittenden, J.C., Miller, J.M. and Gehin, J.L. (1988). Performance of air stripping and granular

activated carbon for synthetic organic chemical and volatile organic chemical removal from groundwater. Drinking

Water Research Division, U.S. Environmental Protection Agency, Cincinnati, Ohio (EPA 600/J-88/053) [cited in

Lykins and Clark, 1994].

Health Canada (2009). Personal communication with K. Taracha, First Nations and Inuit Health Branch, Ottawa,

Ontario.

Health Canada (2011). Unpublished report from Andy Nong, Healthy Environments and Consumer Safety Branch,

Ottawa, Ontario.

Hefner, R.E., Jr., Watanabe, P.G. and Gehring, P.J. (1975a). Percutaneous absorption of vinyl chloride. Toxicol.

Appl. Pharmacol., 34: 529–532.

Hefner, R.E., Jr., Watanabe, P.G. and Gehring, P.J. (1975b). Preliminary studies on the fate of inhaled vinyl chloride

monomer (VCM) in rats. Environ. Health Perspect., 11: 85–95.

Hemminki, K., Lindbohm, M.L., Hemminki, T. and Vainio, H. (1984). Reproductive hazards and plastics industry.

Industrial Hazards of Plastics ans Synthetic Elastomers: Proceedings of the International Symposium on

Occupational Hazards Related to Plastics and Synthetic Elastomers, Espoo, Finland, November 22–27, 1982. J.

Jarvisalo, P. Pfaffli and H. Vainio (eds.)

Heywood, R. and James, R.W. (1978). Assessment of testicular toxicity in laboratory animals. Environ Health

Perspect 24:73-80.


______________________________________________________________________


49

Himeno, S., Okuda, H. and Suzuki, T. (1983). Lack of dominant lethal effects in male CD-1 mice after short-term

and long-term exposures to vinyl chloride monomer. Toxicol. Lett., 16: 47–53.

Ho, S.F., Phoon, W.H., Gan, S.L., and Chan, Y.K. (1991). Persistent liver dysfunction among workers at a vinyl

chloride monomer polymerization plant. J Soc Occup Med 41(1):10-16.

Hoffmann, D., Patrianakos, C., Brunnemann, K.D. and Gori, G.B. (1976). Chromatographic determination of vinyl

chloride in tobacco smoke. Anal. Chem., 48: 47–50.

Hollstein, M., Marion, M.J., Lehman, T., Welsh, J., Harris, C.C., Martel-Planche, G., Kusters, I. and Montesano, R.

(1994). p53 mutations at A:T base pairs in angiosarcomas of vinyl chloride–exposed factory workers.

Carcinogenesis, 15: 1–3.

Holt, S., Roy, G., Mitra, S., Upton, P.B., Bogdanffy, M.S. and Swenberg, J.A. (2000). Deficiency of N-

methylpurine-DNA-glycosylase expression in nonparenchymal cells, the target cell for vinyl chloride and vinyl

fluoride. Mutat. Res., 460: 105–115.

Hopkins, J. (1979). Vinyl chloride—Part 1: Metabolism. Food Cosmet. Toxicol., 17: 403–405.

HSDB (2005). Vinyl Chloride CASRN: 75-01-4. Hazardous Substances Data Bank. National Library of Medicine.

Available at: http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~28k3wZ:1

Hsiaos, T.-J., Wang, J.-D., Yang, P.-M., Yang, P.-C. and Cheng, T.-J. (2004). Liver fibrosis in asymptomatic

polyvinyl chloride workers. J. Occup. Environ. Med., 46: 962–966.

Hsieh, H.-I., Chen, P.-C., Wong, R.-H., Wang, J.-D., Yang, P.-M. and Cheng, T.-J. (2007). Effect of the CYP2E1

genotype on vinyl chloride monomer–induced liver fibrosis among polyvinyl chloride workers. Toxicology, 239:

34–44.

Hüttner, E. and Nikolova, T. (1998). Cytogenetic analysis of peripheral lymphocytes in a population exposed to

vinyl chloride through an accidental release into the environment. Toxicol. Lett., 96–97: 143–148.

IARC (1979). Vinyl chloride, polyvinyl chloride and vinyl chloride–vinyl acetate copolymers. International Agency

for Research on Cancer. IARC Monogr. Eval. Carcinog. Risks Hum., 19: 377.

IARC (2008). 1,3-Butadiene, ethylene oxide and vinyl halides (vinyl fluoride, vinyl chloride and vinyl bromide).

International Agency for Research on Cancer. IARC Monogr. Eval. Carcinog. Risks Hum., 97: 525.

Infante, P.F., Wagoner, J.K. and Waxweiler, R.J. (1976). Carcinogenic, mutagenic and teratogenic risks associated

with vinyl chloride. Mutat. Res., 41: 131–141.

IPCS (1994). Assessing human health risks of chemicals: derivation of guidance values for health-based exposure

limits. International Programme on Chemical Safety, World Health Organization, Geneva (Environmental Health

Criteria 170).

IPCS (1999). Vinyl chloride. International Programme on Chemical Safety, World Health Organization, Geneva. pp.

1–356 (Environmental Health Criteria 215).

IPCS (2005). Chemical-specific adjustment factors for interspecies differences and human variability: guidance

document for use of data in dose/concentration–response assessment. International Programme on Chemical Safety,

World Health Organization, Geneva (Harmonization Project Document No. 2). Available at:

www.inchem.org/documents/harmproj/harmproj/harmproj2.pdf


______________________________________________________________________


50

Jedrychowski, R.A., Sokal, J.A. and Chmielnicka, J. (1985). Comparison of the impact of continuous and

intermittent exposure to vinyl chloride, including phenobarbital effects. J. Hyg. Epidemiol. Microbiol. Immunol.

28:111-120.

Ji, F., Wang, W., Xia, Z.L., Zheng, Y.J., Qiu, Y.L., Wu, F., Miao, W.B., Jin, R.F., Qian, J., Jin, L., Zhu, Y.L. and

Christiani, D.C. (2010). Prevalence and persistence of chromosomal damage, and susceptible genotypes of

metabolic and DNA repair genes in Chinese vinyl chloride–exposed workers. Carcinogenesis, 31(4): 648–653.

Jian, K. and Pintauro, P.N. (1997). Asymmetric PVDF hollow-fiber membranes for organic/water pervaporation. J.

Memb. Sci., 135(1): 41–53.

John, J.A., Smith, F.A. and Schwetz, B.A. (1981). Vinyl chloride: inhalation teratology study in mice, rats and

rabbits. Environ. Health Perspect., 41: 171–177.

Jones, R.D., Smith, D.M. and Thomas, P.G. (1988). A mortality study of vinyl chloride monomer workers employed

in the United Kingdom in 1940–1974. Scand. J. Work Environ. Health, 14: 153–160.

Kappus, H., Bolt, H.M., Buchter, A. and Bolt, W. (1976). Liver microsomal uptake of (14

C)vinyl chloride and

transformation to protein alkylating metabolites in vitro. Toxicol. Appl. Pharmacol., 37: 461–471.

Keppler, F., Borchers, R., Pracht, J., Rheinberger, S. and Schöler, H.F. (2002). Natural formation of vinyl chloride

in the terrestrial environment. Environ. Sci. Technol. 2002, 36, 2479-2483.

Kotseva, K. (1996). Five year follow-up study of the incidence of arterial hypertension and coronary heart disease in

vinyl chloride monomer and polyvinyl chloride production workers. Int. Arch. Occup. Environ. Health, 68: 377–

379.

Krajewski, J., Dobecki, M. and Gromiec, J. (1980). Retention of vinyl chloride in the human lung. Br. J. Ind. Med.,

37: 373–374.

Laib, R.J. and Bolt, H.M. (1977). Alkylation of RNA by vinyl chloride metabolites in vitro and in vivo: formation of

1-N6-etheno-adenosine. Toxicology, 8: 185–195.

Laib, R.J. and Bolt, H.M. (1978). Formation of 3,N4-ethenocytidine moieties in RNA by vinyl chloride metabolities

in vitro and in vivo. Arch. Toxicol., 39: 235–240.

Laib, R.J., Bolt, H.M., Cartier, R., and Bartsch, H. (1989). Increased alkylation of liver DNA and cell turnover in

young versus old rats exposed to vinyl chloride correlates with cancer susceptibility. Toxicol Lett 45:231-239.

Laplanche, A., Clavel-Chapelon, F., Contassot, J.C. and Lanouziere, C. (1992). Exposure to vinyl chloride

monomer: Results of a cohort study after a 7 year follow-up. Br. J. Ind. Med. 49(2):134-137.

Lee, C.C., Bhandari, J.C., Winston, J.M., House, W.B., Dixon, R.L. and Woods, J.S. (1978). Carcinogenicity of

vinyl chloride and vinylidene chloride. J. Toxicol. Environ. Health, 4: 15–30.

Leibman, K.C. (1977.) Current literature: metabolism of vinyl chloride. Drug Metab. Disp. 5:93-94.

Lesage, S., McBride, R.A., Cureton, P.M. and Brown, S. (1993). Fate of organic solvents in landfill leachates under

simulated field conditions and in anaerobic microcosms. Waste Manage. Res., 11: 215–226.

Lewis, R. and Rempala, G. (2003). A case–cohort study of angiosarcoma of the liver and brain cancer at a polymer

production plant. J. Occup. Environ. Med., 45: 538–545.

Lewis, R., Rempala, G., Dell, L.D. and Mundt, K.A. (2003). Vinyl chloride and liver and brain cancer at a polymer

production plant in Louisville, Kentucky. J. Occup. Environ. Med., 45: 533–537.


______________________________________________________________________


51

Lilis, R., Anderson, H., Nicholson, W.J., Daum, S., Fischbein, A.S. and Selikoff, I.J. (1975). Prevalence of disease

among vinyl chloride and polyvinyl chloride workers. Ann. N. Y. Acad. Sci., 246: 22–41.

Little, J.C., Daisey, J.M. and W.W. Nazaroff. (1992). Transport of subsurface contaminants into buildings.

Environmental Science & Technology 26: 2058–2066.

Loprieno, N., Barale, R., Baroncelli, S., Bauer, C., Bronzetti, G., Cammellini, A., Cercignani, G., Corsi, C., Gervasi,

G., Leporini, C., Nieri, R., Rossi, A.M., Stretti, G. and Turchi, G. (1976). Evaluation of the genetic effects induced

by vinyl chloride monomer (VCM) under mammalian metabolic activation: studies in vitro and in vivo. Mutat. Res.,

40: 85–96.

Love, O.T. and Eilers, R.G. (1982). Treatment of drinking water containing trichloroethylene and related industrial

solvents. J. Am. Water Works Assoc., 74(8): 413–425.

Love, O.T., Miltner, R.J., Eilers, R.G. and Fronk-Leist, C.A. (1983). Treatment of volatile organic compounds in

drinking water. Municipal Environmental Research Laboratory, U.S. Environmental Protection Agency, Cincinnati,

Ohio (EPA 600-8-83-019).

Luo, J.C.J., Cheng, T.J., Du, C.L. and Wang, J.D. (2003). Molecular epidemiology of plasma oncoproteins in vinyl

chloride monomer workers in Taiwan. Cancer Detect. Prev., 27: 94–101.

Lykins, B.W., Jr. and Clark, R.M. (1994). US drinking water regulations: treatment technologies and cost. Drinking

Water Research Division, U.S. Environmental Protection Agency, Cincinnati, Ohio (EPA-600/J-94/381).

Malaveille, C., Bartsch, H., Barbin, A., Camus, A.M., Montesano, R., Croisy, A. and Jacquignon, P. (1975).

Mutagenicity of vinyl chloride, chloroethyleneoxide, chloroacetaldehyde and chloroethanol. Biochem. Biophys.

Res. Commun., 63: 363–370.

Maltoni, C., and Cotti, G. (1988). Carcinogenicity of vinyl chloride in Sprague-Dawley rats after prenatal and

postnatal exposure. Ann. NY Acad. Sci. 534:145-159.

Maltoni, C., Lefemine, G., Ciliberti, A., Cotti, G. and Carretti, D. (1981). Carcinogenicity bioassays of vinyl

chloride monomer: a model of risk assessment on an experimental basis. Environ. Health Perspect., 41: 3–29.

Maltoni, C., Clini, C., Vicini, F. and Masina, A. (1984). Two cases of liver angiosarcoma among polyvinyl chloride

(PVC) extruders of an Italian factory producing PVC bags and other containers. Am. J. Ind. Med., 5: 297–302.

Marion, M.J. and Boivin-Angele, S. (1999). Vinyl chloride–specific mutations in humans and animals. IARC Sci.

Publ., 150: 315–324.

Marion, M.J., Froment, O. and Trepo, C. (1991). Activation of Ki-ras gene by point mutation in human liver

angiosarcoma associated with vinyl chloride exposure. Mol. Carcinog., 4: 450–454.

Marques, C.A., Selva, M. and Tundo, P. (1994). Facile hydrodehalogenation with H2 and Pd/C catalyst under

multiphase conditions. 2. Selectivity and kinetics. J. Org. Chem., 59: 3830–3837.

Mastangelo, G., Fedeli, U., Fadda, E., Milan, G., Turato, A. and Pavanello, S. (2003). Lung cancer risk in workers

exposed to poly(vinyl chloride) dust: a nested case-referent study. Occup Environ Med 60: 423-428.

Mastangelo, G., Fedeli, U. and Martines, D. (2008). Hepatocellular carcinoma and vinyl chloride. Letter to the

editor. Cancer Causes Control. DOI 10.1007/s10552-008-9268-9.


______________________________________________________________________


52

Matsuda, T., Yagi, T., Kawanishi, M., Matsui, S. and Takebe, H. (1995). Molecular analysis of mutations induced

by 2-chloroacetaldehyde, the ultimate carcinogenic form of vinyl chloride, in human cells using shuttle vectors.

Carcinogenesis 16(10) pp: 2389-2394.

MDNR (2006). Controlling vinyl chloride in distribution systems. Minnesota Department of Natural Resources.

Water Protection Program Technical Bulletin 6/2006. Available at: www.dnr.mo.gov/pubs/pub2123.pdf

Ministère du Développement durable, de l’Environnement et des Parcs du Québec (2009). Personal communication

with C. Robert.

Monson, R.R., Peters, J.M. and Johnson, M.N. (1975). Proportional mortality among vinyl chloride workers.

Environ. Health Perspect., 11: 75–77.

Morinello, E.J., Ham, A.J., Ranasinghe, A., Nakamura, J., Upton, P.B. and Swenberg, J.A. (2002a). Molecular

dosimetry and repair of N2,3-ethenoguanine in rats exposed to vinyl chloride. Cancer Res., 62: 5189–5195.

Morinello, E.J., Koc, H., Ranasinghe, A. and Swenberg, J.A. (2002b). Differential induction of N2,3-ethenoguanine

in rat brain and liver after exposure to vinyl chloride. Cancer Res., 62, 5183–5188.

Mundt, K.A., Dell, L.D., Austin, R.P., Luippold, R.S., Noess, R. and Bigelow, C. (2000). Historical cohort study of

10 109 men in the North American vinyl chloride industry, 1942–72: update of cancer mortality to 31 December

1995. Occup. Environ. Med., 57: 774–781.

New Brunswick Department of Environment (2009). Personal communication with K. White.

NHMRC (2004). Australian drinking water guidelines. National Health and Medical Research Council. Available at:

www.nhmrc.gov.au/publications/synopses/eh19syn.htm

Nova Scotia Department of Environment (2009). Personal communication with C.L. Mosher.

NRCC (2010). National Plumbing Code. National Research Council of Canada, Ottawa, Ontario. Available at:

www.nrc-cnrc.gc.ca/eng/services/irc/codes-centre.html

NPRI (2007). Reviewed Facility Data Release. National Pollutant Release Inventory. Environment Canada, Ottawa.

Available at: www.ec.gc.ca/inrp-npri/default.asp?lang=en&n=00C79591-1

NSF/ANSI (2012). NSF International/American National Standards Institute Standard 61: Drinking water system

components—health effects. NSF International, Ann Arbor, Michigan.

OEHHA (2000). Public health goals for chemicals in drinking water: Vinyl chloride in drinking water. Office of

Environmental Health Hazard Assessment, California Environmental Protection Agency, Sacramento, California

(OEHHA.1-46).

OME (1997). C-15 guidelines for use at contaminated sites in Ontario. Ontario Ministry of the Environment,

Toronto, Ontario.

Otson, R., Williams, D.T. and Biggs, D.C. (1982). Relationships between raw water quality, treatment, and

occurrence of organics in Canadian potable water. Bull. Environ. Contam. Toxicol., 28: 396–403.

Parsons, F., Wood, P.R. and DeMarco, J. (1984). Transformations of tetrachloroethene and trichloroethene in

microcosms and groundwater. J. Am. Water Works Assoc., 26: 56–59.

Peng, M., Vane, L.M. and Liu, S.X. (2003). Recent advances in VOCs removal from water by pervaporation. J.

Hazard. Mater., 98(1): 69–90.


______________________________________________________________________


53

Perrard, M.H. (1985). Mutagenicity and toxicity of chloroethylene oxide and chloroacetaldehyde. Experientia, 41:

676–677.

Pessayre, D., Wandscheer, J.C., Descatoire, V., Artigou, J.Y., and Benhamou, J.P. (1979). Formation and

inactivation of a chemically reactive metabolite of vinyl chloride. Toxicol. Appl. Pharmacol. 49:505-515.

Pirastu, R., Comba, P., Reggiani, A., Foa, V., Masina, A. and Maltoni, C. (1990). Mortality from liver disease

among Italian vinyl chloride monomer/polyvinyl chloride manufacturers. Am. J. Ind. Med., 17: 155–161.

Pirastu, R., Baccini, M., Biggeri, A. and Comba, P. (2003). [Epidemiological study of workers exposed

to vinyl chloride in a Porto Marghera factory: Mortality update.] Epidemiol. Prev., 27: 161–172. (Article (in Italian).

Popper, H. and Thomas, L.B. (1975). Alterations of liver and spleen among workers exposed to vinyl chloride. Ann.

N. Y. Acad. Sci., 246: 172–194.

Prodan, L,, Suciu, I,, Pislaru, V., Ilea, E. and Pascu, L. (1975). Experimental acute toxicity of vinyl chloride

(monochloroethene). Ann N Y Acad Sci 246:154-8.

Purchase, I.F., Stafford, J. and Paddle, G.M. (1985). Vinyl chloride—a cancer case study. In: Toxicological risk

assessment. Vol. 2. D. Krewski (ed.). CRC Press, Boca Raton, Florida. p. 167.

Rannug, U., Johansson, A., Ramel, C. and Wachtmeister, C. (1974). The mutagenicity of vinyl chloride after

metabolic activation. Ambio, 3: 194–197.

Rannug, U., Gothe, R. and Wachtmeister, C.A. (1976). The mutagenicity of chloroethylene oxide,

chloroacetaldehyde, 2-chloroethanol and chloroacetic acid, conceivable metabolites of vinyl chloride. Chem. Biol.

Interact., 12: 251–263.

Reynolds, E.S., Moslen, M.T., Szabo, S., Jaeger, R.J. and Murphy, S.D. (1975). Hepatotoxicity of vinyl chloride and

1,1-dichloroethylene. Role of mixed function oxidase system. Am. J. Pathol., 81: 219–236.

Rice, J.M. (1981). Prenatal susceptibility to carcinogenesis by xenobiotic substances including vinyl chloride.

Environ Health Perspect 41:179-88.

Richardson, R. and Edwards, M. (2009). Vinyl chloride and organotin stabilizers in water contacting new and aged

PVC pipes. Water Research Foundation, Denver, Colorado (Web Report No. 2991).

Sabadie, N., Malaveille, C., Camus, A. and Bartsch, H. (1980). Comparison of the hydroxylation of benzo(a)pyrene

with the metabolism of vinyl chloride, N-nitrosomorpholine, and N-nitroso-N′-methylpiperazine to mutagens by

human and rat liver microsomal fractions. Cancer Res., 40: 119–126.

Saskatchewan Ministry of Environment (2009). Personal communication with S. Ferris.

SCC (2011). Directory of accredited product and service certification bodies. Standards Council of Canada, Ottawa,

Ontario. Available at: www.scc.ca/en/programs-services/product-certification/directory-of-accredited-clients

Schoental, R. and Magee, P.N. (1957). Chronic liver changes in rats after a single dose of lasiocarpine, a

pyrrolizidine (Senecio) alkaloid. J. Pathol. Bacteriol., 74: 305–319.

Schoental, R. and Magee, P.N. (1959). Further observations on the subacute and chronic liver changes in rats after a

single dose of various pyrrolizidine (Senecio) alkaloids. J. Pathol. Bacteriol., 78: 471–482.

Schwammlein, K. and Leitzke, O. (1995). Field test for the elimination of chlorinated hydrocarbons compounds in

groundwater by combined oxidation process. In: Proceedings of the 12th Ozone World Congress, May 1995.

International Ozone Association, Lille, France. p. 325-336


______________________________________________________________________


54

Shreir, G.C. and Reinhard, M. (1995). Catalytic hydrodehalogenation of chlorinated ethylenes using palladium

hydrogen for the treatment of contaminated water. Chemosphere, 31(6): 3475–3487.

Simonato, L., L’Abbé, K.A., Andersen, A., Belli, S., Comba, P., Engholm, G., Ferro, G., Hagmar, L., Langard, S.,

Lundberg, I., Piratsu, R., Thomas, P., Winkelmann, R. and Saracci, R. (1991). A collaborative study of cancer

incidence and mortality among vinyl chloride workers. Scand. J. Work Environ. Health, 17: 159–169.

Sinués, B., Sanz, A., Bernal, M.L., Tres, A., Lanuza, J., Ceballos, C. and Sáenz, M.S. (1991). Sister chromatid

exchanges, proliferating rate index, and micronuclei in biomonitoring of internal exposure to vinyl chloride

monomer in plastic industry workers. Toxicol. Appl. Pharmacol., 108: 37–45.

Smith, S.J., Li, Y., Whitley, R., Marion, M.J., Partilo, S., Carney, W.P. and Brandt-Rauf, P.W. (1998). Molecular

epidemiology of p53 protein mutations in workers exposed to vinyl chloride. Am. J. Epidemiol., 147: 302–308.

Sokal, J.A., Baranski, B., Majka, J., Rolecki, R., Stetkiewicz, J., lvanova-Chemishanska, L., Vergieva, T., Antonov,

G., Mirkova, E., Kolakowski, A., Szendzikowski, S. and Wróblewska, K. (1980). Experimental studies on the

chronic toxic effects of vinyl chloride in rats. J. Hyg. Epidemiol. Microbiol. Immunol. 24:285-294.

Stephens, R.D., Ball, N.B. and Mar, D.M. (1986). A multimedia study of hazardous waste landfill gas migration. In:

Pollutants in a Multimedia Environment, Y. Cohen (Ed.), Plenum Press, New York, New York pp. 265-287.

Stocco, C., MacNeill, M., Wang, D., Xu, X., Guay, M., Brook, J. and Wheeler, A.J. (2008). Predicting personal

exposure of Windsor, Ontario residents to volatile organic compounds using indoor measurements and survey data.

Atmos. Environ., 42: 5905–5912.

Swenberg, J.A., Fedtke, N., Ciroussel, F., Barbin, A. and Bartsch, H. (1992). Etheno adducts formed in DNA of

vinyl chloride–exposed rats are highly persistent in liver. Carcinogenesis, 13: 727–729.

Swenberg, J.A., Bogdanffy, M.S., Ham, A., Holt, S., Kim, A., Morinello, E.J., Ranasinghe, A., Scheller, N. and

Upton, P.B. (1999). Formation and repair of DNA adducts in vinyl chloride– and vinyl fluoride–induced

carcinogenesis. IARC Sci. Publ., 150: 29–43.

Swenberg, J.A., Ham, A., Koc, H., Morinello, E., Ranasinghe, A., Tretyakova, N., Upton, P.B. and Wu, K. (2000).

DNA adducts: effects of low exposure to ethylene oxide, vinyl chloride and butadiene. Mutat. Res., 464: 77–86.

Tarkowski , S, Wisniewska-Knypl, J.M., Klimczak, J., Draminski, W. and Wroblewska, K. (1980). Urinary

excretion of thiodigylcolic acid and hepatic content of free thiols in rats at different levels of exposure to vinyl

chloride. J. Hyg. Epidemiol. Microbiol. Immunol. 24:253-261.

Theriault, G., and Allard, P. (1981). Cancer mortality of a group of Canadian workers exposed to vinyl chloride

monomer. J Occup Med 23:671-676.

Theriault, G., Iturra, H. and Gingras, S. (1983). Evaluation of the association between birth defects and exposure to

ambient vinyl chloride. Teratology, 27: 359–370.

Thornton, S.R., Schroeder, R.E., Robison, R.L., Rodwell, D.E., Penney, D.A., Nitschke, K.D. and Sherman, W.K.

(2002). Embryo-fetal developmental and reproductive toxicology of vinyl chloride in rats. Toxicol. Sci., 68: 207–

219.

Til, H.P., Immel, H.R. and Feron, V.J. (1983). Lifespan oral carcinogenicity study of vinyl chloride in rats (final

report). CIVO Institutes, TNO, Delft, Netherlands (Report No. V 83.285/291099).

Til, H.P., Feron, V.J. and Immel, H.R. (1991). Lifetime (149-week) oral carcinogenicity study of vinyl chloride in

rats. Food Chem. Toxicol., 29: 713–718.


______________________________________________________________________


55

Torkelson, R.R., Oyen, F. and Rowe, V.K. (1961). The toxicity of vinyl chloride as determined by repeated

exposure of laboratory animals. Am. J. Hyg., 22: 354–361.

Trivers, G.E., Cawley, H.L., DeBenedetti, V.M., Hollstein, M., Marion, M.J., Bennett, W.P., Hoover, M.L., Prives,

C.C., Tamburro, C.C. and Harris, C.C. (1995). Anti-p53 antibodies in sera of workers occupationally exposed to

vinyl chloride. J. Natl. Cancer Inst., 87: 1400–1407.

Uragami, T., Yamada, H. and Miyata, T. (2001). Removal of dilute volatile organic compounds in water through

graft copolymer membranes consisting of poly (alkylmethacrylate) and poly (dimethylsiloxane) by pervaporation

and their membrane morphology. J. Memb. Sci., 187(1): 255–269.

U.S. EPA (1985a). National Primary Drinking Water Regulations—Synthetic organic chemicals; monitoring for

unregulated contaminants; final rule. Fed. Regist. 50(219):46902.

U.S. EPA (1985b). Technologies and costs for the removal of volatile organic chemicals from potable water

supplies. U.S. Environmental Protection Agency, Washington, DC [cited in U.S. EPA, 1998].

U.S. EPA (1987a). National Primary Drinking Water Regulations—Synthetic organic chemicals, monitoring for

unregulated contaminants; final rule. Fed. Regist., 52(130): 25690.

U.S. EPA (1987b). Vinyl chloride. Health advisory draft. Office of Drinking Water, U.S. Environmental Protection

Agency, Washington, DC, March 31, 1987 (EPA 820-D-87-001).

U.S. EPA (1991). Technologies for upgrading existing or designing new drinking water treatment facilities. Center

for Environmental Research Information, Office of Drinking Water, U.S. Environmental Protection Agency,

Cincinnati, Ohio.

U.S. EPA (1995). Methods for determinations of organic compounds in drinking water - Supplement III. U.S.

Environmental Protection Agency, Office of Research and Development, EPA/600/R-95/131, Washington, DC

U.S. EPA (1998). Small system compliance technology list for the non-microbial contaminants regulated before

1996. Office of Water, U.S. Environmental Protection Agency, Washington, DC (EPA 815-R-98-002).

U.S. EPA (2000a). EPIsuite version 3.11. U.S. Environmental Protection Agency. Updated version 4.10. Available

at: www.epa.gov/oppt/exposure/pubs/episuite.htm.

U.S. EPA (2000b). Toxicological review of vinyl chloride (CAS No. 75-01-4) in support of summary information

on the Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency, Washington, DC, May.

pp. 1–197. Available at: www.epa.gov/iris/toxreviews/1001tr.pdf

U.S. EPA (2003). Analytical feasibility support document for the six year review of existing National Primary

Drinking Water Regulations (reassessment of feasibility for chemical contaminants). Targeting and Analysis

Branch, Standards and Risk Management Division, Office of Groundwater and Drinking Water, U.S. Environmental

Protection Agency, Washington, DC (EPA 815-R-03-003). Available at:

www.epa.gov/safewater/standard/review/pdfs/support_6yr_analytical_final.pdf

U.S. EPA (2009a). Measurement of purgeable organic compounds in water by capillary column gas

chromatography/mass spectrometry. Technical Support Center, Office of Groundwater and Drinking Water, U.S.

Environmental Protection Agency, Cincinnati, Ohio (EPA 815-B-09-009).

U.S. EPA (2009b). Analytical feasibility support document for the second six-year review of existing National

Primary Drinking Water Regulations. Office of Water, U.S. Environmental Protection Agency, Cincinnati, Ohio

(EPA 815-B-09-003).


______________________________________________________________________


56

U.S. EPA (2009c). Water treatment technologies feasibility support document for chemical contaminants for the

second six-year review of National Primary Drinking Water Regulations. Office of Water, U.S. Environmental

Protection Agency, Cincinnati, Ohio (EPA 815-B-09-007).

U.S. EPA (2009d). Development of estimated quantitation levels for the second six-year review of National Primary

Drinking Water Regulations. Office of Water, U.S. Environmental Protection Agency, Cincinnati, Ohio (EPA 815-

B-09-005).

U.S. EPA (2010). Benchmark dose software (BMDS) version 2.1.1. U.S. Environmental Protection Agency,

Washington, DC. Available at: www.epa.gov/ncea/bmds/about.html

Verburgt, F.G. and Vogel, E. (1977). Vinyl chloride mutagenesis in Drosophila melanogaster. Mutat. Res., 48: 327–

336.

Verschueren, K. (1984). Handbook of environmental data on organic chemicals. Van Nostrand Reinhold Co.

Viola, P.L., Bigotti, A. and Caputo, A. (1971). Oncogenic response of rat skin, lungs, and bones to vinyl chloride.

Cancer Res., 31: 516–522.

von Gunten, U. (2003). Ozonation of drinking water: Part 1. Oxidation kinetics and product formation. Wat. Res.,

37: 1443–1467.

Oxy Vinyl (2008). Personal communication with M. Waher. Oxy Vinyl, Thorold, Ontario.

Walles, S.A. and Holmberg, B. (1984). Induction of single-strand breaks in DNA of mice after inhalation of vinyl

chloride. Cancer Lett., 25: 13–18.

Walter, R.K., Lin, P., Edwards, M. and Richardson, E. (2011). Investigation of factors affecting the accumulation of

vinyl chloride in polyvinyl chloride piping used in drinking water distribution system. Water Res., 45: 2607–2645.

Ward, E., Boffetta, P., Andersen, A., Colin, D., Comba, P., Deddens, J.A., De Santis, M., Engholm, G., Hagmar, L.,

Langard, S., Lundberg, I., McElvenny, D., Piratsu, R., Sali, D., and Simonato, L. (2001). Update of the Follow-Up

of Mortality and Cancer Incidence among European Workers Employed in the Vinyl Chloride Industry,

Epidemiology: 12(6), pp 710-718.

Watanabe, P.G. and Gehring, P.J. (1976). Dose-dependent fate of vinyl chloride and its possible relationship to

oncogenicity in rats. Environ. Health Perspect., 17: 145–152.

Watanabe, P.G., McGowan, G.R. and Gehring, P.J. (1976a). Fate of [14

C]vinyl chloride after single oral

administration in rats. Toxicol. Appl. Pharmacol., 36: 339–352.

Watanabe, P.G., McGowan, G.R., Madrid, E.O. and Gehring, P.J. (1976b). Fate of [14

C]vinyl chloride following

inhalation exposure in rats. Toxicol. Appl. Pharmacol., 37: 49–59.

Watanabe, P.G., Hefner, R.E., Jr. and Gehring, P.J. (1976c). Vinyl chloride-induced depression of hepatic non-

protein sulfhydryl content and effects on bromosulphalein (BSP) clearance in rats. Toxicology 6:1-8.

Waxweiler, R.J., Stringer, W., Wagoner, J.K., Jones, J., Falk, H. and Carter, C. (1976). Neoplastic risk among

workers exposed to vinyl chloride. Ann. N. Y. Acad. Sci., 271: 40–48.

Weihrauch, M., Lehnert, G., Kockerling, F., Wittekind, C. and Tannapfel, A. (2000). p53 mutation pattern in

hepatocellular carcinoma in workers exposed to vinyl chloride. Cancer, 88: 1030–1036.


______________________________________________________________________


57

Weihrauch, M., Benicke, M., Lehnert, G., Wittekind, C., Wrbitzky, R. and Tannapfel, A. (2001). Frequent k-ras-2

mutations and p16INK4A

methylation in hepatocellular carcinomas in workers exposed to vinyl chloride. Br. J.

Cancer, 84: 982–989.

Weihrauch, M., Bader, M., Lehnert, G., Koch, B., Wittekind, C., Wrbitzky, R. and Tannapfel, A. (2002). Mutation

analysis of K-ras-2 in liver angiosarcoma and adjacent nonneoplastic liver tissue from patients occupationally

exposed to vinyl chloride. Environ. Mol. Mutagen., 40: 36–40.

WHO (2004). Vinyl chloride in drinking water. Background document for development of WHO Guidelines for

Drinking-water Quality. World Health Organization, Geneva. pp. 1–23. Available at:

www.who.int/water_sanitation_health/dwq/chemicals/vinylchloride.pdf

WHO (2011). Guidelines for drinking-water quality. 4th edition. World Health Organization, Geneva.

Whysner, J., Conaway, C.C., Verna, L. and Williams, G.M. (1996). Vinyl chloride mechanistic data and risk

assessment: DNA reactivity and cross-species quantitative risk extrapolation. Pharmacol. Ther., 71: 7–28.

Withey, J.R. (1976). Pharmacodynamics and uptake of vinyl chloride monomer administered by various routes to

rats. J. Toxicol. Environ. Health, 1: 381–394.

Wolf, K., Holland, R. and Rajaratnam, A. (1987). Vinyl chloride contamination: the hidden threat. J. Hazard. Mater.,

15: 163–184.

Wong, O., Whorton, M.D., Foliart, D.E. and Ragland, D. (1991). An industry-wide epidemiologic study of vinyl

chloride workers, 1942–1982. Am. J. Ind. Med., 20: 317–334.

Wong, R.H., Chen, P.C., Du, C.L., Wang, J.D. and Cheng, T.J. (2002). An increased standardised mortality ratio for

liver cancer among polyvinyl chloride workers in Taiwan. Occup. Environ. Med., 59: 405–409.

Wong, R.H., Wang, J.D., Hsieh, L.L. and Cheng, T.J. (2003). XRCC1, CYP2E1 and ALDH2 genetic

polymorphisms and sister chromatid exchange frequency alterations amongst vinyl chloride monomer–exposed

polyvinyl chloride workers. Arch. Toxicol., 77: 433–440.

Yoon, M., Madden, M.C. and Barton, H.A. (2007). Extrahepatic metabolism by CYP2E1 in PBPK modeling of

lipophilic volatile organic chemicals: impacts on metabolic parameter estimation and prediction of dose metrics, J.

Toxicol. Environ. Health, Part A 70 pp. 1527–1541.

Zhong, L., Zhan, H. and Kuo, C. (2002). Advanced oxidation and degradation of vinyl chloride in water. Chem.

Eng. Technol., 25(4): 433–437.


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Appendix A: List of acronyms

ALARA as low as reasonably achievable

ANSI American National Standards Institute

AOP advanced oxidation process

ASL angiosarcoma of the liver

bw body weight

CAA chloroacetaldehyde

CEO chloroethylene oxide

CI confidence interval

CPVC chlorinated polyvinyl chloride

CSA Canadian Standards Association

CYP cytochrome P450

DNA deoxyribonucleic acid

ELCD electrolytic conductivity detector

EPA Environmental Protection Agency (U.S.)

EQL estimated quantitation limit

GAC granular activated carbon

GC gas chromatography

GSH glutathione

HBV health-based value

HCC hepatocellular carcinoma

IARC International Agency for Research on Cancer

LD50 median lethal dose

LOD limit of detection

LOQ limit of quantification

MDL method detection limit

MRL minimum reporting level

MS mass spectrometer/spectrometry

NADPH reduced nicotinamide adenine dinucleotide phosphate

NOAEL no-observed-adverse-effect level

NPC National Plumbing Code

NSF NSF International

PBPK physiologically based pharmacokinetic

PID photoionization detector

POD point of departure

PQL practical quantification limit

PTA packed tower aeration

PVC polyvinyl chloride

RNA ribonucleic acid

RR relative risk

SCC Standards Council of Canada

SIM selected ion monitoring

SMR standardized mortality ratio

SPAC single product allowable concentration

TDI tolerable daily intake


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UV ultraviolet

VOC volatile organic compound

WHO World Health Organization

Water Vinyl Chloride Chloride Vinyle Eau ENG - Canada

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